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Amyloid PET Imaging in Lewy Body Disorders

      Lewy body (LB) disorders, including Parkinson disease (PD), Parkinson disease dementia (PDD), and dementia with Lewy bodies (DLB), are the second most common type of neurodegenerative dementia. Although the pathological hallmarks of LB disorders are Lewy bodies and Lewy neurites, cortical amyloid-beta (Aβ) deposition is also often seen. The relationship between Aβ pathology and dementia in LB disorders is unclear. Recently, positron emission tomography Aβ ligands have been developed that enable in vivo imaging of Aβ. In this paper we review amyloid imaging studies in LB disorders. LB disorders are associated with lower mean cortical Aβ ligand binding compared with Alzheimer disease. In DLB and PDD many subjects have normal levels of cortical Aβ, though a subset show increased Aβ ligand binding. Those with DLB show greater ligand binding than PDD; binding does not appear to be increased in PD without dementia. Cortical Aβ deposition may be a factor in the development of cognitive impairment in some cases of dementia in LB disorders. Amyloid imaging is of limited use in the diagnosis of LB disorders but Aβ deposition may predict the future development of dementia in PD. Reports of correlation between Aβ deposition and symptom profile, severity, and progression have been inconsistent. Some results suggest a synergistic interaction between Aβ and α-synuclein. Interpretation of the current evidence is hampered by differing methodologies across studies and small sample sizes. Large, prospective longitudinal studies are needed to clarify the association of Aβ with symptom development, progression, severity, and treatment response in LB disorders.

      Key Words

      Lewy body (LB) disorders include Parkinson disease (PD) and the Lewy body dementias, dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD). Following Alzheimer disease (AD), LB dementias are the second most common cause of neurodegenerative dementia, with DLB alone accounting for around 15% of cases at postmortem
      • McKeith I.G.
      • Galasko D.
      • Kosaka K.
      • et al.
      Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop.
      and 10% in clinical samples,
      • Stevens T.
      • Livingston G.
      • Kitchen G.
      • et al.
      Islington study of dementia subtypes in the community.
      and high rates of dementia observed in PD.
      • Emre M.
      • Aarsland D.
      • Brown R.
      • et al.
      Clinical diagnostic criteria for dementia associated with Parkinson's disease.
      DLB and PDD are both characterized by dementia syndromes with specific associated symptoms including parkinsonism, fluctuating cognition, and visual hallucinations.
      • Emre M.
      • Aarsland D.
      • Brown R.
      • et al.
      Clinical diagnostic criteria for dementia associated with Parkinson's disease.
      • McKeith I.G.
      • Dickson D.W.
      • Lowe J.
      • et al.
      Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.
      Based on international consensus, DLB is diagnosed when dementia develops without parkinsonism or within a year of the development of parkinsonism; PDD is diagnosed when parkinsonism precedes dementia by more than one year.
      • Emre M.
      • Aarsland D.
      • Brown R.
      • et al.
      Clinical diagnostic criteria for dementia associated with Parkinson's disease.
      • McKeith I.G.
      • Dickson D.W.
      • Lowe J.
      • et al.
      Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.
      There are no other major clinical differences between DLB and PDD, and despite some controversy surrounding the “one-year rule” they are generally recognized to be on a continuum of LB disease.
      • McKeith I.
      Commentary: DLB and PDD: the same or different? Is there a debate?.
      The pathological hallmarks of LB disorders are Lewy bodies and Lewy neurites, but many cases also display AD pathology (amyloid-β [Aβ] plaques and neurofibrillary tangles [NFTs]) post mortem.
      • Kovari E.
      • Horvath J.
      • Bouras C.
      Neuropathology of Lewy body disorders.
      The importance of AD pathology in LB disorders and its relationship to cognitive impairment is unclear. Postmortem studies of confirmed DLB cases have reported that concurrent AD pathology measured by increased NFTs was associated with a lower likelihood of visual hallucinations and a lower chance of a DLB diagnosis during life.
      • Merdes A.R.
      • Hansen L.A.
      • Jeste D.V.
      • et al.
      Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies.
      • Weisman D.
      • Cho M.
      • Taylor C.
      • et al.
      In dementia with Lewy bodies, Braak stage determines phenotype, not Lewy body distribution.
      A combination of AD and LB pathology in dementia is associated with a lower occurrence of parkinsonism and hallucinations compared with LB pathology alone.
      • Del Ser T.
      • Hachinski V.
      • Merskey H.
      • et al.
      Clinical and pathologic features of two groups of patients with dementia with Lewy bodies: effect of coexisting Alzheimer-type lesion load.
      Greater cortical Aβ pathology has been associated with increased cognitive impairment
      • Nelson P.T.
      • Kryscio R.J.
      • Jicha G.A.
      • et al.
      Relative preservation of MMSE scores in autopsy-proven dementia with Lewy bodies.
      and a shorter time from onset of parkinsonian symptoms to cognitive impairment
      • Ballard C.
      • Ziabreva I.
      • Perry R.
      • et al.
      Differences in neuropathologic characteristics across the Lewy body dementia spectrum.
      • Fujishiro H.
      • Iseki E.
      • Higashi S.
      • et al.
      Distribution of cerebral amyloid deposition and its relevance to clinical phenotype in Lewy body dementia.
      • Selikhova M.
      • Williams D.R.
      • Kempster P.A.
      • et al.
      A clinico-pathological study of subtypes in Parkinson's disease.
      in LB disorders. DLB has been associated with a greater Aβ burden than PDD and PD.
      • Fujishiro H.
      • Iseki E.
      • Higashi S.
      • et al.
      Distribution of cerebral amyloid deposition and its relevance to clinical phenotype in Lewy body dementia.
      • Aarsland D.
      • Ballard C.G.
      • Halliday G.
      Are Parkinson's disease with dementia and dementia with Lewy bodies the same entity?.
      • Jellinger K.A.
      • Seppi K.
      • Wenning G.K.
      Clinical and neuropathological correlates of Lewy body disease.
      It has been suggested that the co-occurrence of AD and LB pathology represents more than coincidence, and that there may be synergism, with Aβ increasing the propensity of α-synuclein to accumulate and aggregate.
      • Pletnikova O.
      • West N.
      • Lee M.K.
      • et al.
      Abeta deposition is associated with enhanced cortical alpha-synuclein lesions in Lewy body diseases.
      Postmortem studies are by their nature cross-sectional and tend to report end-stage disease. Thus patients with initial “pure Lewy body pathology” may be found post mortem to have significant AD pathology, although this may not have been related to their initial presentation. Positron emission tomography (PET) amyloid imaging, initially with 11C-PiB (Pittsburgh compound B) and now with
      • Sojkova J.
      • Driscoll I.
      • Iacono D.
      • et al.
      In vivo fibrillar beta-amyloid detected using [11C]PiB positron emission tomography and neuropathologic assessment in older adults.
      F labeled compounds, was developed to measure brain Aβ burden in vivo.
      • Rowe C.C.
      • Villemagne V.L.
      Brain amyloid imaging.
      Postmortem studies have demonstrated that amyloid imaging with these ligands correlates well with Aβ deposition in the form of neuritic and diffuse plaques, and amyloid angiopathy.
      • Sojkova J.
      • Driscoll I.
      • Iacono D.
      • et al.
      In vivo fibrillar beta-amyloid detected using [11C]PiB positron emission tomography and neuropathologic assessment in older adults.
      • Clark C.M.
      • Schneider J.A.
      • Bedell B.J.
      • et al.
      Use of florbetapir-PET for imaging beta-amyloid pathology.
      • Ikonomovic M.D.
      • Klunk W.E.
      • Abrahamson E.E.
      • et al.
      Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease.
      Aβ deposition in vivo is consistently elevated in AD, and also in some healthy control subjects.
      • Quigley H.
      • Colloby S.J.
      • O'Brien J.T.
      PET imaging of brain amyloid in dementia: a review.
      • Rosenberg P.B.
      • Wong D.F.
      • Edell S.L.
      • et al.
      Cognition and amyloid load in Alzheimer disease imaged with florbetapir F 18(AV-45) positron emission tomography.
      The objective of this paper was to review all studies to date that have involved amyloid imaging in LB disorders to examine the contribution of Aβ pathology to these disorders.
      Terminology in this research field has been a subject of some debate.
      • McKeith I.
      Commentary: DLB and PDD: the same or different? Is there a debate?.
      In this paper we use the terminology accepted by recent consensus statements detailed above.
      • Emre M.
      • Aarsland D.
      • Brown R.
      • et al.
      Clinical diagnostic criteria for dementia associated with Parkinson's disease.
      • McKeith I.G.
      • Dickson D.W.
      • Lowe J.
      • et al.
      Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.
      LB disorders refers to all LB pathologies (in this paper generally PD [± mild cognitive impairment], PDD, and DLB).

      Methods

      A Medline (Web of Knowledge; 1950–present) search was carried out in January 2013. The search algorithm used was: (“Amyloid”) AND (“Positron emission tomography” OR “PET”) AND (“Lewy” OR “Parkinson disease”). Each word was entered both as a ‘topic’ and ‘MeSH’ term; lemmatization was used. Eighty-two English-language results were found. Titles and abstracts were then screened by two reviewers (PD and AT) to identify studies that performed amyloid brain imaging in patients with Lewy body disease. A total of 16 studies with original data were identified (Table 1 summarizes these papers). Four papers reporting postmortem findings in patients who had antemortem amyloid PET scans were also included. Two further In Press studies available online came to the authors' attention and were included. Reference lists from the selected articles were searched for any additional references not captured by the search, though none were found.
      Table 1Summary of PET Amyloid Imaging Studies Excluding Neuropathological Case Studies
      StudyPopulationSourceScans, LigandAmyloid PET Acquisition and Image AnalysisRegions ReportedMajor Findings
      Rowe et al. 2007
      • Rowe C.C.
      • Ng S.
      • Ackermann U.
      • et al.
      Imaging beta-amyloid burden in aging and dementia.
      10 DLB

      17 AD

      9 MCI

      6 FTD

      27 HC
      AD/DLB: memory disorders and neurobehavioural clinics.

      Controls: from a separate longitudinal study known to have normal cognitive function.
      MRI

      11C-PIB PET
      90 min acquisition. ROI 11C-PIB DVR v. cerebellum. Logan graphical analysis method.16 cortical and subcortical areas including overall cortex.PiB burden AD>DLB>HC.

      PiB burden correlated with shorter time from onset of symptoms to diagnosis in DLB.

      ApoE4 genotype linked to Aβ burden across groups.
      Edison et al. 200823,
      Includes 10 DLB patients from Rowe et al.30
      13 DLB
      Includes 10 DLB patients from Rowe et al.30


      12 PDD

      10 PD

      41 HC
      Multicenter study (UK, Finland, Australia).MRI

      11C-PIB PET
      60-90 min 11C-PIB uptake ratio; ROI v. cerebellum.

      Voxel-based comparison with threshold p <0.001.
      6 cortical areas, striatum, thalamus and whole cortex.DLB more likely to show raised Aβ burden compared with PDD or PD.
      Gomperts et al. 2008
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      8 DLB

      7 PDD

      11 PD

      15 AD

      37 HC
      Movement and memory units.

      AD and HC collected separately in another longitudinal study.
      11C-PIB PET60 min DVR v cerebellum. Logan graphical analysis method.6 cortical areas, striatum, whole cortex.PiB binding DLB>PDD/PD/HC.

      PiB binding in DLB comparable to AD.

      In LBD (DLB+PDD) relative striatal binding was associated with improved performance on UPDRS.
      Johansson et al. 2008
      • Johansson A.
      • Savitcheva I.
      • Forsberg A.
      • et al.
      [(11)C]-PIB imaging in patients with Parkinson's disease: preliminary results.
      5 PD

      16 AD

      6 HC
      AD and HC from previous study.

      PD: not stated.
      11C-PIB PET

      11C-L-DOPA PET
      40–60 min regional uptake volume of interest v. cerebellum.5 cortical areas, subcortical white matter, pons, striatum.PiB retention was greater in AD than PD in all cortical areas and striatum. Lower in PD than control in frontal, parietal and cingulate areas.
      Maetzler et al. 2008
      • Maetzler W.
      • Reimold M.
      • Liepelt I.
      • et al.
      [11C]PIB binding in Parkinson's disease dementia.
      10 PDD

      6 AD

      11 HC
      Not stated.11C-PIB PET42–72 min ROI SUVR v. cerebellum.Frontal cortex, posterior cingulate, striatum, thalamus, brainstem, cerebellum, white matter2/10 PDD had “AD-like” pattern of amyloid deposition.

      Brainstem:posteriorcingulate DVR: PDD>control, AD, “AD-like” PD.
      Maetzler et al. 2009
      • Maetzler W.
      • Liepelt I.
      • Reimold M.
      • et al.
      Cortical PIB binding in Lewy body disease is associated with Alzheimer-like characteristics.
      9 DLB

      12 PDD

      14 PD
      Ward/OP dept. in neurodegenerative dept. of a university hospital.11C-PIB PET42–72 min ROI SUVR v. cerebellum.5 cortical areas, whole cortex, striatum.PiB positive patients had lower CSF Aβ42, higher ApoE4 allele rate, all had dementia. Within dementia, PiB positive had lower MMSE scores.
      Jokinen et al. 2010
      • Jokinen P.
      • Scheinin N.
      • Aalto S.
      • et al.
      [(11)C]PIB-, [(18)F]FDG-PET and MRI imaging in patients with Parkinson's disease with and without dementia.
      11 PDD

      8 PD

      24 HC
      University hospital.11C-PIB PET

      18F-FDG PET

      MRI
      60–90 min 11C-PIB uptake

      ROI v. cerebellum.
      5 cortical areas, caudate, putamen.No significant difference between groups in any cortical area. PDD more likely to show 1+ cortical areas with increased PiB uptake.
      Foster et al. 2010
      • Foster E.R.
      • Campbell M.C.
      • Burack M.A.
      • et al.
      Amyloid imaging of Lewy body-associated disorders.
      6 DLB

      15 PDD

      9 PD-MCI

      8 PD

      9 HC
      Movement disorders center.11C-PIB PET

      MRI
      60 min dynamic scan. Binding potentials of ROIs and MCBP. Logan graphical analysis, cerebellum as reference.5 cortical areas, caudate, mean cortex.No differences in MCBP or regional BPs between groups.

      Correlation between caudate BP/MCBP and MMSE in some groups.
      Burke et al. 2011
      • Burke J.F.
      • Albin R.L.
      • Koeppe R.A.
      • et al.
      Assessment of mild dementia with amyloid and dopamine terminal positron emission tomography.
      14 DLB

      36 AD

      25 FTD
      Cognitive disorders clinic.11C-PIB PET

      11C-DTBZ PET
      80 min scan. ROI DVR v. cerebellum. Subjective visual assessment.Frontal cortex : white matter DVR ratio.Only moderate concordance between clinical diagnosis and diagnosis based on scan results.
      Claasen et al. 2011
      • Claassen D.O.
      • Lowe V.J.
      • Peller P.J.
      • et al.
      Amyloid and glucose imaging in dementia with Lewy bodies and multiple systems atrophy.
      3 DLB

      3 MSA

      12 HC
      Neurology clinic.11C-PIB PET

      18F-FDG PET

      MRI
      40–60 min acquisition. ROI v. cerebellum.7 cortical areas and caudate.Higher binding found in DLB in all areas. Most marked in prefrontal, parietal, temporal, and precuneus.
      Villemagne et al. 2011
      • Villemagne V.L.
      • Ong K.
      • Mulligan R.S.
      • et al.
      Amyloid Imaging with F-18-Florbetaben in Alzheimer Disease and Other Dementias.
      7 DLB

      5 PD

      30 AD

      20 MCI

      11 FTD

      4 VaD

      32 HC
      Memory disorders service, movement disorders clinics.18F-Florbetaben PET

      MRI
      90–110 min acquisition.

      ROI SUVR v. cerebellar cortex
      9 cortical areas, total cortex, 6 non-cortical areas.AD and MCI had higher neocortical and striatal binding than controls. No other significant differences between groups.
      Gomperts et al. 2012
      • Gomperts S.N.
      • Locascio J.J.
      • Marquie M.
      • et al.
      Brain amyloid and cognition in Lewy body diseases.
      18 DLB

      12 PDD

      14 PD-MCI

      29 PD

      85 HC
      Movement disorders and memory disorders units. HCS from separate study.11C-PIB PET60 min dynamic acquisition. Logan graphical analysis method. ROI DVR v. cerebellum.

      SPM analysis corrected for multiple comparisons (false discovery rate).
      Precuneus

      Voxel-wise comparison.
      DLB exhibited higher binding than other groups, particularly in frontal and parietal areas. No differences found between non-DLB groups.

      PiB burden increased in ApoE4 genotype across entire cohort.

      In DLB increased PiB binding was associated with decreased MMSE score and poorer semantic memory.
      Graff-Radford et al. 2012
      • Graff-Radford J.
      • Boeve B.F.
      • Pedraza O.
      • et al.
      Imaging and acetylcholinesterase inhibitor response in dementia with Lewy bodies.
      7 DLB (of 54 DLB)AD research center (retrospective study of pts. involved in longitudinal study).11C-PIB PET

      MRI
      40–60 min. ROI v. cerebellum.

      Partial volume correction.
      Global cortical retention.Both subjects who declined were PiB positive; all 3 subjects who improved were PiB negative.
      Kantarci et al. 2012
      • Kantarci K.
      • Lowe V.J.
      • Boeve B.F.
      • et al.
      Multimodality imaging characteristics of dementia with Lewy bodies.
      21 DLB

      21 AD

      42 HC
      DLB recruited from AD research centre. AD and HC from a longitudinal cohort.11C-PIB PET

      18F-FDG PET

      MRI
      40–60 min acquisition.

      ROI v. cerebellum.

      Voxel based comparison using FWE correction. Partial volume correction.
      Global cortical retention.

      Voxel-wise comparison.
      DLB PiB binding was significantly lower than AD but significantly higher than controls.

      No relationship found between global PiB and motor impairment, dementia rating, visual hallucinations or duration of symptoms.
      Petrou et al. 2012
      • Petrou M.
      • Bohnen N.I.
      • Muller M.L.
      • et al.
      Abeta-amyloid deposition in patients with Parkinson disease at risk for development of dementia.
      40 PD at risk for dementiaUniversity-based movement disorders subspecialty clinic.11C-PIB PET

      11C-DTBZ PET

      MRI
      80 min acquisition. Logan graphical analysis method.

      DVR v. cerebellum.
      Mean cortical PiB DVR.

      Visual assessment.
      Cortical PiB was inversely correlated with overall cognitive score and WAIS score.
      Ossenkoppele et al. 2013

      Ossenkoppele R, Prins ND, Pijnenburg YA, et al: Impact of molecular imaging on the diagnostic process in a memory clinic. Alzheimers Dement 2013; 9:414–421

      66 AD

      30 MCI

      15 SMC

      18 FTD

      5 DLB

      20 other
      Specialist memory disorder clinic. Patients mostly attending for second/third opinion.11C-PIB PET

      18F-FDG PET

      MRI
      90 min dynamic scan. ROI BP v. cerebellum.

      For 12 patients 60–90 min SUVR ROI v. cerebellum.
      Visual assessment.11C-PIB PET contributed to diagnostic process in 86% of patients, mainly used to rule out AD.
      Shimada et al. 2013

      Shimada H, Shinotoh H, Hirano S, et al: Beta-amyloid in Lewy body disease is related to Alzheimer's disease-like atrophy. Mov Disord 2013; 28:169–175

      8 DLB

      7 PDD

      13 AD

      22 HC
      Not stated.11C-PIB PET

      MRI
      90 min dynamic scan. Logan graphical analysis method.

      VOI DVR v. cerebellum.
      Mean cortical PiB DVR.

      4 cortical areas.
      PiB positive LBD subjects demonstrated cortical atrophy compared with HC; greater atrophy in parahippocampal regions than PiB negative LBD subjects.
      Gomperts et al. 2013
      • Gomperts S.N.
      • Locascio J.J.
      • Rentz D.
      • et al.
      Amyloid is linked to cognitive decline in patients with Parkinson disease without dementia.
      35 PD

      11 PD-MCI
      Not stated.11C-PIB PET60 min dynamic scan. Logan graphical analysis method. DVR v. cerebellum.Precuneus, frontal cortex, and striatum.Higher PiB retention at baseline associated with progression to MCI or dementia and with deterioration in executive function.

      Motor deterioration not linked to baseline striatal or precuneus amyloid burden.
      Notes: DLB: dementia with Lewy bodies; PD(D): Parkinson disease (dementia); LBD: Lewy body dementias (DLB/PDD); AD: Alzheimer disease; MSA: multisystem atrophy; FTD: frontotemporal dementia; VaD: vascular dementia; MCI: mild cognitive impairment; HC: healthy controls; SMC: subjective memory complaint; PET: positron emission tomography; MRI: magnetic resonance imaging; PiB: Pittsburgh compound B; DTBZ: dihydrotetrabenazine; FDG: fluorodeoxyglucose; ROI: region of interest; SUVR: standardised uptake value ratio; MCBP: mean cortical binding potential; DVR: distribution volume ratio; SPM: statistical parametric mapping; FWE: family-wise error.
      a Includes 10 DLB patients from Rowe et al.
      • Rowe C.C.
      • Ng S.
      • Ackermann U.
      • et al.
      Imaging beta-amyloid burden in aging and dementia.

      Results

      Dementia with Lewy Bodies

      When compared with healthy controls, four studies found DLB to be associated with significantly greater cortical and subcortical 11C-PiB binding on PET imaging.
      • Edison P.
      • Rowe C.C.
      • Rinne J.O.
      • et al.
      Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography.
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      • Gomperts S.N.
      • Locascio J.J.
      • Marquie M.
      • et al.
      Brain amyloid and cognition in Lewy body diseases.
      • Kantarci K.
      • Lowe V.J.
      • Boeve B.F.
      • et al.
      Multimodality imaging characteristics of dementia with Lewy bodies.
      A 32% greater uptake was found in one study,
      • Edison P.
      • Rowe C.C.
      • Rinne J.O.
      • et al.
      Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography.
      although six controls with raised 11C-PiB binding had been excluded from analysis, as the aim of the study was to examine patterns of raised Aβ deposition in LB disorders.
      Two studies failed to find a significant difference between DLB and controls in global or regional Aβ ligand binding.
      • Foster E.R.
      • Campbell M.C.
      • Burack M.A.
      • et al.
      Amyloid imaging of Lewy body-associated disorders.
      • Villemagne V.L.
      • Ong K.
      • Mulligan R.S.
      • et al.
      Amyloid Imaging with F-18-Florbetaben in Alzheimer Disease and Other Dementias.
      In both, DLB displayed greater binding (mean cortical binding potential: 0.18 versus 0.08
      • Foster E.R.
      • Campbell M.C.
      • Burack M.A.
      • et al.
      Amyloid imaging of Lewy body-associated disorders.
      ; neocortex standardized uptake value ratio: 1.38 versus 1.26
      • Villemagne V.L.
      • Ong K.
      • Mulligan R.S.
      • et al.
      Amyloid Imaging with F-18-Florbetaben in Alzheimer Disease and Other Dementias.
      ). It should be noted that these studies contained smaller DLB samples (N = 6 and N = 7, respectively) than those that found significant differences (N = 8–21
      • Edison P.
      • Rowe C.C.
      • Rinne J.O.
      • et al.
      Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography.
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      • Gomperts S.N.
      • Locascio J.J.
      • Marquie M.
      • et al.
      Brain amyloid and cognition in Lewy body diseases.
      • Kantarci K.
      • Lowe V.J.
      • Boeve B.F.
      • et al.
      Multimodality imaging characteristics of dementia with Lewy bodies.
      ).
      Particular areas of increased Aβ ligand binding have included frontal, parietal, and cingulate areas, along with the striatum,
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      • Gomperts S.N.
      • Locascio J.J.
      • Marquie M.
      • et al.
      Brain amyloid and cognition in Lewy body diseases.
      • Kantarci K.
      • Lowe V.J.
      • Boeve B.F.
      • et al.
      Multimodality imaging characteristics of dementia with Lewy bodies.
      • Claassen D.O.
      • Lowe V.J.
      • Peller P.J.
      • et al.
      Amyloid and glucose imaging in dementia with Lewy bodies and multiple systems atrophy.
      • Rowe C.C.
      • Ng S.
      • Ackermann U.
      • et al.
      Imaging beta-amyloid burden in aging and dementia.
      with relative sparing of the medial temporal lobe.
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      • Kantarci K.
      • Lowe V.J.
      • Boeve B.F.
      • et al.
      Multimodality imaging characteristics of dementia with Lewy bodies.
      • Rowe C.C.
      • Ng S.
      • Ackermann U.
      • et al.
      Imaging beta-amyloid burden in aging and dementia.
      Four studies have compared amyloid brain imaging in DLB and AD. The largest study (N = 42) found global 11C-PiB retention ratio to be significantly lower in DLB.
      • Kantarci K.
      • Lowe V.J.
      • Boeve B.F.
      • et al.
      Multimodality imaging characteristics of dementia with Lewy bodies.
      Two other studies have also found lower cortical Aβ ligand binding in DLB compared with AD
      • Villemagne V.L.
      • Ong K.
      • Mulligan R.S.
      • et al.
      Amyloid Imaging with F-18-Florbetaben in Alzheimer Disease and Other Dementias.
      • Rowe C.C.
      • Ng S.
      • Ackermann U.
      • et al.
      Imaging beta-amyloid burden in aging and dementia.
      (distribution volume ratio: 1.7 versus 2.0;
      • Rowe C.C.
      • Ng S.
      • Ackermann U.
      • et al.
      Imaging beta-amyloid burden in aging and dementia.
      standardized uptake value ratio: 1.38 versus 1.93
      • Villemagne V.L.
      • Ong K.
      • Mulligan R.S.
      • et al.
      Amyloid Imaging with F-18-Florbetaben in Alzheimer Disease and Other Dementias.
      ).
      One study found no difference between DLB and AD, with very similar results in both groups in all cortical areas.
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      In that study, the DLB group was on average 9 years older than the AD group, with significantly greater cognitive impairment, although results held after adjusting for age, though not cognition, in multivariate analysis.
      Gomperts et al.
      • Gomperts S.N.
      • Locascio J.J.
      • Marquie M.
      • et al.
      Brain amyloid and cognition in Lewy body diseases.
      compared DLB with the other Lewy body disorders: PDD, PD with mild cognitive impairment (PD-MCI) and PD. The study compared precuneus 11C-PIB retention, as retention was particularly high in this region and correlated very highly with global retention (r = 0.939).
      • Gomperts S.N.
      • Locascio J.J.
      • Marquie M.
      • et al.
      Brain amyloid and cognition in Lewy body diseases.
      Mean precuneus 11C-PiB distribution volume ratio was significantly higher in DLB than the other Lewy body disorders (DLB: 1.49, PDD: 1.28, PD-MCI: 1.16, PD: 1.16). This echoed their earlier findings of higher global cortical 11C-PiB retention in DLB.
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      Edison et al.
      • Edison P.
      • Rowe C.C.
      • Rinne J.O.
      • et al.
      Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography.
      also reported higher 11C-PiB binding in DLB compared with PDD and PD, but did not report direct statistical testing between the groups. Another study comparing three DLB patients and three with multiple systems atrophy found higher cortical 11C-PiB binding in the DLB group.
      • Claassen D.O.
      • Lowe V.J.
      • Peller P.J.
      • et al.
      Amyloid and glucose imaging in dementia with Lewy bodies and multiple systems atrophy.
      Two studies found no difference in Aβ ligand binding between DLB and PD28 (cortical standardized uptake value ratio: DLB = 1.38, PD = 1.14); or between DLB, PD, PD-MCI and PDD
      • Foster E.R.
      • Campbell M.C.
      • Burack M.A.
      • et al.
      Amyloid imaging of Lewy body-associated disorders.
      (mean cortical binding potential: DLB = 0.18, PDD = 0.11, PD-MCI = 0.08, PD = 0.04). In both studies, although not significant, Aβ ligand binding in the groups bore the same relationship to each other seen in studies that did find a significant difference (DLB > PDD > PD).
      When present, the pattern of Aβ ligand binding in Lewy body disorders is similar to that seen in AD,
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      • Kantarci K.
      • Lowe V.J.
      • Boeve B.F.
      • et al.
      Multimodality imaging characteristics of dementia with Lewy bodies.
      • Rowe C.C.
      • Ng S.
      • Ackermann U.
      • et al.
      Imaging beta-amyloid burden in aging and dementia.
      • Maetzler W.
      • Reimold M.
      • Liepelt I.
      • et al.
      [11C]PIB binding in Parkinson's disease dementia.
      • Petrou M.
      • Bohnen N.I.
      • Muller M.L.
      • et al.
      Abeta-amyloid deposition in patients with Parkinson disease at risk for development of dementia.
      • Maetzler W.
      • Liepelt I.
      • Reimold M.
      • et al.
      Cortical PIB binding in Lewy body disease is associated with Alzheimer-like characteristics.

      Shimada H, Shinotoh H, Hirano S, et al: Beta-amyloid in Lewy body disease is related to Alzheimer's disease-like atrophy. Mov Disord 2013; 28:169–175

      although one study found occipital cortex binding relative to overall binding to be lower in AD.
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      Some studies divided each diagnostic group into Aβ-positive and Aβ-negative subgroups, based on a defined threshold of Aβ ligand binding. There was a consistent finding of higher rates of Aβ-positive subjects in AD than DLB, in DLB than PDD, and in PDD than controls or PD (overall average: AD = 78%, DLB = 57%, PDD = 35%, control = 21%, PD = 13%; Table 2). The findings of PD versus controls were variable, with some finding higher rates in PD,
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      • Foster E.R.
      • Campbell M.C.
      • Burack M.A.
      • et al.
      Amyloid imaging of Lewy body-associated disorders.
      others in controls.
      • Edison P.
      • Rowe C.C.
      • Rinne J.O.
      • et al.
      Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography.
      • Villemagne V.L.
      • Ong K.
      • Mulligan R.S.
      • et al.
      Amyloid Imaging with F-18-Florbetaben in Alzheimer Disease and Other Dementias.
      • Jokinen P.
      • Scheinin N.
      • Aalto S.
      • et al.
      [(11)C]PIB-, [(18)F]FDG-PET and MRI imaging in patients with Parkinson's disease with and without dementia.
      Table 2Cortical Amyloid Burden Classification (Positive or Negative) by Diagnostic Group
      StudyDLBPDDPDPD-MCIADControlMethod of Classification
      +ve−ve+ve−ve+ve−ve+ve−ve+ve−ve+ve−ve
      Edison et al. 2008
      • Edison P.
      • Rowe C.C.
      • Rinne J.O.
      • et al.
      Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography.
      ,
      Includes control subjects that were excluded from analysis because of high cortical Aβ ligand binding.
      112210010----6
      Includes control subjects that were excluded from analysis because of high cortical Aβ ligand binding.
      41PiB uptake ratio >2 SD above control mean in 1 or more cortical regions.
      Gomperts et al. 2008
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      717074--1501918DVR >1.3 in 50+ cortical voxels.
      Maetzler et al. 2008
      • Maetzler W.
      • Reimold M.
      • Liepelt I.
      • et al.
      [11C]PIB binding in Parkinson's disease dementia.
      --28----66011Visual inspection.
      Maetzler et al. 2009
      • Maetzler W.
      • Liepelt I.
      • Reimold M.
      • et al.
      Cortical PIB binding in Lewy body disease is associated with Alzheimer-like characteristics.
      4548014------SUVR >1.45/<1.38.
      Jokinen et al. 2010
      • Jokinen P.
      • Scheinin N.
      • Aalto S.
      • et al.
      [(11)C]PIB-, [(18)F]FDG-PET and MRI imaging in patients with Parkinson's disease with and without dementia.
      --3808----222Cortical SUVR >1.5 in 1 or more cortical regions.
      Foster et al. 2010
      • Foster E.R.
      • Campbell M.C.
      • Burack M.A.
      • et al.
      Amyloid imaging of Lewy body-associated disorders.
      244111718--18MCBP ≥0.2.
      Villemagne et al. 2011
      • Villemagne V.L.
      • Ong K.
      • Mulligan R.S.
      • et al.
      Amyloid Imaging with F-18-Florbetaben in Alzheimer Disease and Other Dementias.
      25--05--291527SUVR >1.4.
      Graff-Radford et al. 2012
      • Graff-Radford J.
      • Boeve B.F.
      • Pedraza O.
      • et al.
      Imaging and acetylcholinesterase inhibitor response in dementia with Lewy bodies.
      34----------Global cortical PiB retention ratio >1.5.
      Kantarci et al. 2012
      • Kantarci K.
      • Lowe V.J.
      • Boeve B.F.
      • et al.
      Multimodality imaging characteristics of dementia with Lewy bodies.
      1110------192933Global cortical PiB retention ratio >1.5.
      Petrou et al. 2012
      • Petrou M.
      • Bohnen N.I.
      • Muller M.L.
      • et al.
      Abeta-amyloid deposition in patients with Parkinson disease at risk for development of dementia.
      --4105228----Visual inspection.
      Ossenkoppele et al. 2013

      Ossenkoppele R, Prins ND, Pijnenburg YA, et al: Impact of molecular imaging on the diagnostic process in a memory clinic. Alzheimers Dement 2013; 9:414–421

      ,
      Includes control subjects that were excluded from analysis because of high cortical Aβ ligand binding.
      41------4026--Visual inspection.
      Shimada et al. 2013

      Shimada H, Shinotoh H, Hirano S, et al: Beta-amyloid in Lewy body disease is related to Alzheimer's disease-like atrophy. Mov Disord 2013; 28:169–175

      4425----1305
      Includes control subjects that were excluded from analysis because of high cortical Aβ ligand binding.
      17DVR >2 SD above HC mean in one or more cortical region.
      Total483628518533361223547177
      % +ve57351387821
      Notes: +ve: positive; −ve: negative; PiB: Pittsburgh compound-B; DVR: distribution volume ratio; MCBP: mean cortical binding potential; SUVR: standard uptake volume ratio.
      a Includes control subjects that were excluded from analysis because of high cortical Aβ ligand binding.
      Comparison across studies, and the amalgamation of data used here, should be treated with some caution as studies used different outcome measures (binding potential, distribution volume ratio, standardized uptake value ratio, visual inspection) and, perhaps more importantly, set different criteria for identifying cases as Aβ-positive or -negative (some looked at whole cortex average, in others increased Aβ in one cortical area sufficed). For example, seven of the eight total Aβ-positive PD patients came from one study that accounted for only 18% of the total PD group.
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      Recruitment practices should also be taken into account. For example, some studies selected patients well known to the investigators with no sign of cognitive impairment
      • Johansson A.
      • Savitcheva I.
      • Forsberg A.
      • et al.
      [(11)C]-PIB imaging in patients with Parkinson's disease: preliminary results.
      or patients with particularly characteristic symptoms.
      • Rowe C.C.
      • Ng S.
      • Ackermann U.
      • et al.
      Imaging beta-amyloid burden in aging and dementia.
      Although this is understandable, particularly in studies where sample sizes are likely to be low or where etiopathological differences between disorders are being investigated and thus “pure” cases are sought, it does mean that the samples may not necessarily be representative of the total population with that disease.

      Parkinson Disease Dementia

      All six studies comparing Aβ ligand binding in PDD and controls found no significant difference between the two groups.
      • Edison P.
      • Rowe C.C.
      • Rinne J.O.
      • et al.
      Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography.
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      • Gomperts S.N.
      • Locascio J.J.
      • Marquie M.
      • et al.
      Brain amyloid and cognition in Lewy body diseases.
      • Foster E.R.
      • Campbell M.C.
      • Burack M.A.
      • et al.
      Amyloid imaging of Lewy body-associated disorders.
      • Maetzler W.
      • Reimold M.
      • Liepelt I.
      • et al.
      [11C]PIB binding in Parkinson's disease dementia.
      • Jokinen P.
      • Scheinin N.
      • Aalto S.
      • et al.
      [(11)C]PIB-, [(18)F]FDG-PET and MRI imaging in patients with Parkinson's disease with and without dementia.
      Foster et al. found a mean cortical binding potential of 0.11 in PDD compared with 0.08 in controls.
      • Foster E.R.
      • Campbell M.C.
      • Burack M.A.
      • et al.
      Amyloid imaging of Lewy body-associated disorders.
      In general, PDD results were very similar to controls, with a tendency toward a small number of outliers in the PDD group with high levels of cortical Aβ.
      • Edison P.
      • Rowe C.C.
      • Rinne J.O.
      • et al.
      Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography.
      • Gomperts S.N.
      • Locascio J.J.
      • Marquie M.
      • et al.
      Brain amyloid and cognition in Lewy body diseases.
      • Foster E.R.
      • Campbell M.C.
      • Burack M.A.
      • et al.
      Amyloid imaging of Lewy body-associated disorders.
      • Maetzler W.
      • Liepelt I.
      • Reimold M.
      • et al.
      Cortical PIB binding in Lewy body disease is associated with Alzheimer-like characteristics.
      Maetzler et al.
      • Maetzler W.
      • Reimold M.
      • Liepelt I.
      • et al.
      [11C]PIB binding in Parkinson's disease dementia.
      compared PDD and AD after removing two PDD patients with markedly raised 11C-PiB binding that they felt indicated a different disease entity to “pure” PDD. The remaining PDD subjects demonstrated remarkably similar cortical Aβ binding to the control group and lower cortical and striatal binding than the AD group .The two high 11C-PiB binding subjects had an “AD-like” pattern of deposition. The only other study to compare PDD and AD found no outlying PDD subjects, with Aβ ligand binding significantly lower in PDD than AD.
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      Several studies have noted no significant difference in Aβ binding between PDD and PD
      • Edison P.
      • Rowe C.C.
      • Rinne J.O.
      • et al.
      Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography.
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      • Gomperts S.N.
      • Locascio J.J.
      • Marquie M.
      • et al.
      Brain amyloid and cognition in Lewy body diseases.
      • Foster E.R.
      • Campbell M.C.
      • Burack M.A.
      • et al.
      Amyloid imaging of Lewy body-associated disorders.
      • Jokinen P.
      • Scheinin N.
      • Aalto S.
      • et al.
      [(11)C]PIB-, [(18)F]FDG-PET and MRI imaging in patients with Parkinson's disease with and without dementia.
      or PD-MCI PDD consistently has a greater proportion of Aβ-positive subjects, however, when groups are divided in a binary fashion as positive or negative (Table 2).
      Relevant to this, Petrou et al.
      • Petrou M.
      • Bohnen N.I.
      • Muller M.L.
      • et al.
      Abeta-amyloid deposition in patients with Parkinson disease at risk for development of dementia.
      identified 40 patients with PD at risk for dementia (with MCI/older age/long duration of PD/prominent gait or balance impairments). On further testing 5 out of 40 subjects were diagnosed as having mild dementia. When the subjects underwent amyloid imaging four of five subjects with dementia had elevated 11C-PiB binding on visual inspection, compared with 2 of 30 patients with PD-MCI and zero of 5 with PD and some other risk factor for dementia. This finding of increased rates of Aβ-positive subjects in PDD groups compared with PD or controls—without any difference in mean cortical Aβ ligand binding—may be accounted for by a subgroup of outlying PDD subjects with high Aβ binding,
      • Edison P.
      • Rowe C.C.
      • Rinne J.O.
      • et al.
      Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography.
      • Gomperts S.N.
      • Locascio J.J.
      • Marquie M.
      • et al.
      Brain amyloid and cognition in Lewy body diseases.
      • Foster E.R.
      • Campbell M.C.
      • Burack M.A.
      • et al.
      Amyloid imaging of Lewy body-associated disorders.
      • Maetzler W.
      • Liepelt I.
      • Reimold M.
      • et al.
      Cortical PIB binding in Lewy body disease is associated with Alzheimer-like characteristics.
      or a different pattern of deposition in PDD that results in focal increases in binding without a significantly increased overall Aβ load.
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.

      Parkinson Disease

      Seven studies have compared amyloid imaging findings in PD and controls. One small study compared a group of PD patients with controls from a previous study and found the PD group had significantly lower 11C-PiB binding in the frontal (11C-PiB uptake/cerebellum: 1.10 versus 1.30), parietal (1.15 versus 1.35), and posterior cingulate (1.04 versus 1.43) cortices.
      • Johansson A.
      • Savitcheva I.
      • Forsberg A.
      • et al.
      [(11)C]-PIB imaging in patients with Parkinson's disease: preliminary results.
      The PD subjects were well known to the investigators, with no evidence of cognitive impairment on routine assessment. It may be that they represented a subgroup of particularly cognitively healthy individuals.
      Other studies have found no difference between PD and controls,
      • Edison P.
      • Rowe C.C.
      • Rinne J.O.
      • et al.
      Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography.
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      • Gomperts S.N.
      • Locascio J.J.
      • Marquie M.
      • et al.
      Brain amyloid and cognition in Lewy body diseases.
      • Foster E.R.
      • Campbell M.C.
      • Burack M.A.
      • et al.
      Amyloid imaging of Lewy body-associated disorders.
      • Villemagne V.L.
      • Ong K.
      • Mulligan R.S.
      • et al.
      Amyloid Imaging with F-18-Florbetaben in Alzheimer Disease and Other Dementias.
      • Jokinen P.
      • Scheinin N.
      • Aalto S.
      • et al.
      [(11)C]PIB-, [(18)F]FDG-PET and MRI imaging in patients with Parkinson's disease with and without dementia.
      although mean cortical Aβ ligand binding was marginally lower in PD in some
      • Gomperts S.N.
      • Locascio J.J.
      • Marquie M.
      • et al.
      Brain amyloid and cognition in Lewy body diseases.
      • Foster E.R.
      • Campbell M.C.
      • Burack M.A.
      • et al.
      Amyloid imaging of Lewy body-associated disorders.
      • Villemagne V.L.
      • Ong K.
      • Mulligan R.S.
      • et al.
      Amyloid Imaging with F-18-Florbetaben in Alzheimer Disease and Other Dementias.
      (mean cortical binding potential: 0.04 versus 0.08,27 standardized uptake value ratio: 1.14 versus 1.26
      • Villemagne V.L.
      • Ong K.
      • Mulligan R.S.
      • et al.
      Amyloid Imaging with F-18-Florbetaben in Alzheimer Disease and Other Dementias.
      ). Edison et al. found similar 11C-PiB uptake in all brain areas (0%–4% higher in PD than controls) although six 11C-PiB positive subjects were removed from the control group before analysis.
      • Edison P.
      • Rowe C.C.
      • Rinne J.O.
      • et al.
      Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography.
      Three studies comparing PD with AD have all found lower brain Aβ ligand binding in PD.
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      • Villemagne V.L.
      • Ong K.
      • Mulligan R.S.
      • et al.
      Amyloid Imaging with F-18-Florbetaben in Alzheimer Disease and Other Dementias.
      • Johansson A.
      • Savitcheva I.
      • Forsberg A.
      • et al.
      [(11)C]-PIB imaging in patients with Parkinson's disease: preliminary results.

      Relationship between Aβ and Clinical Picture

      Cognitive impairment and dementia severity

      Two studies have found a significant correlation between MMSE score and Aβ ligand binding when analyzing data across multiple disease groups (DLB, PDD, PD: r = –0.5, p = 0.01, N = 26
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      ; DLB, PD, AD, MCI, frontotemporal lobar degeneration, vascular dementia, controls: r = −0.49, p <0.0001, N = 109
      • Villemagne V.L.
      • Ong K.
      • Mulligan R.S.
      • et al.
      Amyloid Imaging with F-18-Florbetaben in Alzheimer Disease and Other Dementias.
      ). Over both studies, however, only the MCI group in Villemgne et al.
      • Villemagne V.L.
      • Ong K.
      • Mulligan R.S.
      • et al.
      Amyloid Imaging with F-18-Florbetaben in Alzheimer Disease and Other Dementias.
      displayed the same correlation within the group (r = −0.76, p <0.0001, N = 20).
      Other studies have considered PDD/DLB as a single group for analysis. In such a group the Aβ-positive subjects were found to have a significantly lower MMSE than the Aβ-negative group, but this group was also older.
      • Maetzler W.
      • Liepelt I.
      • Reimold M.
      • et al.
      Cortical PIB binding in Lewy body disease is associated with Alzheimer-like characteristics.
      Conversely, Foster et al.
      • Foster E.R.
      • Campbell M.C.
      • Burack M.A.
      • et al.
      Amyloid imaging of Lewy body-associated disorders.
      were not able to identify differences between Aβ-positive and Aβ-negative PDD/DLB groups in MMSE, Neuropsychiatric Inventory score, or cognitive fluctuations. Pooling the Aβ-positive and Aβ-negative PDD/DLB subjects (N = 21), however, the authors found mean cortical and caudate Aβ binding correlated modestly with MMSE (cortical: r = −0.47, p = 0.04; caudate: r = −0.44, p = 0.05) and clinical dementia rating (CDR) global (cortical: r = 0.55, p = 0.01; caudate: r = 0.51, p = 0.02). No such correlation existed in PD or control groups. In PD-MCI MMSE correlated strongly with caudate Aβ (r = −0.82, p = 0.007, N = 9) but not mean cortical Aβ (p = 0.52).
      In a population mostly consisting of PD-MCI, Aβ ligand binding was found to correlate with global cognitive scores (r = −0.55, p = 0.0006, N = 40) and Wechsler Adult Intelligence Scale score (r = −0.54, p = 0.0004, n = 40).
      • Petrou M.
      • Bohnen N.I.
      • Muller M.L.
      • et al.
      Abeta-amyloid deposition in patients with Parkinson disease at risk for development of dementia.
      These results may have been strongly influenced by four PDD subjects with high levels of brain Aβ and cognitive impairment, however.
      In a DLB-only group, Gomperts et al.
      • Gomperts S.N.
      • Locascio J.J.
      • Marquie M.
      • et al.
      Brain amyloid and cognition in Lewy body diseases.
      found increased Aβ ligand binding to be associated with lower MMSE (p <0.001) scores and worse semantic memory (p = 0.001). No such association was found in PDD, PD, PD-MCI, or controls. Other studies have found no relationship between Aβ and MMSE
      • Edison P.
      • Rowe C.C.
      • Rinne J.O.
      • et al.
      Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography.

      Shimada H, Shinotoh H, Hirano S, et al: Beta-amyloid in Lewy body disease is related to Alzheimer's disease-like atrophy. Mov Disord 2013; 28:169–175

      or dementia severity measured by CDR
      • Kantarci K.
      • Lowe V.J.
      • Boeve B.F.
      • et al.
      Multimodality imaging characteristics of dementia with Lewy bodies.
      in DLB.
      One longitudinal study in 46 PD subjects with either MCI or no cognitive impairment found that baseline increased precuneus 11C-PiB binding was related to decline in executive function (p = 0.035), weakly related to decline in visuospatial function (p = 0.06), and associated with a greater likelihood of transition to MCI or dementia (p = 0.035).
      • Gomperts S.N.
      • Locascio J.J.
      • Rentz D.
      • et al.
      Amyloid is linked to cognitive decline in patients with Parkinson disease without dementia.
      In summary, there is conflicting evidence surrounding the association of amyloid deposition with increased cognitive impairment in LB disorders. Where correlation has been reported, it has generally been modest, and often in samples containing disparate diagnostic groups. Further research is needed to clarify the association of amyloid deposition with cognitive impairment in each of the LB disorders.

      Parkinsonism

      In DLB and PDD, but not PD, higher relative Aβ ligand binding in the striatum (adjusted for overall binding) was associated in one study with better motor performance as measured by the Unified Parkinson's Disease Rating Scale (DLB: r = −0.87, p = 0.01, N = 8; PDD: r = −0.90, p = 0.005, N = 7).
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      Other studies have found no correlation between global cortical
      • Kantarci K.
      • Lowe V.J.
      • Boeve B.F.
      • et al.
      Multimodality imaging characteristics of dementia with Lewy bodies.
      • Foster E.R.
      • Campbell M.C.
      • Burack M.A.
      • et al.
      Amyloid imaging of Lewy body-associated disorders.
      • Maetzler W.
      • Liepelt I.
      • Reimold M.
      • et al.
      Cortical PIB binding in Lewy body disease is associated with Alzheimer-like characteristics.

      Shimada H, Shinotoh H, Hirano S, et al: Beta-amyloid in Lewy body disease is related to Alzheimer's disease-like atrophy. Mov Disord 2013; 28:169–175

      or precuneus
      • Gomperts S.N.
      • Locascio J.J.
      • Marquie M.
      • et al.
      Brain amyloid and cognition in Lewy body diseases.
      Aβ binding and motor impairment. These studies did not report specifically assessing relative striatal binding, however. A longitudinal study found that baseline striatal or precuneus amyloid ligand binding in PD and PD-MCI did not predict future motor deterioration.
      • Gomperts S.N.
      • Locascio J.J.
      • Rentz D.
      • et al.
      Amyloid is linked to cognitive decline in patients with Parkinson disease without dementia.

      Hallucinations and visuospatial ability

      In the two studies which have reported this, no relationship has been found between mean cortical
      • Kantarci K.
      • Lowe V.J.
      • Boeve B.F.
      • et al.
      Multimodality imaging characteristics of dementia with Lewy bodies.
      or occipital
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      Aβ binding and hallucinations.
      In DLB, PDD, and PD, but not AD or controls, relative parietal/posterior cingulate (but not occipital) binding was associated with impaired visuoperceptual ability as measured by the Benton Visual Form Discrimination Test.
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.

      Fluctuations

      Fluctuations, measured using the Mayo Fluctuations Questionnaire, were not found to be associated with an increased Aβ ligand binding in DLB or PDD in two studies.
      • Kantarci K.
      • Lowe V.J.
      • Boeve B.F.
      • et al.
      Multimodality imaging characteristics of dementia with Lewy bodies.
      • Foster E.R.
      • Campbell M.C.
      • Burack M.A.
      • et al.
      Amyloid imaging of Lewy body-associated disorders.

      Rapid eye movement sleep behavior disorder

      No studies have reported investigating an association between rapid eye movement sleep behavior disorder and Aβ ligand binding.

      Disease onset, progression, and treatment response

      The first study of amyloid PET in DLB found that increased Aβ binding was correlated with a shorter time between the onset of cognitive impairment and diagnosis of DLB (r = −0.75, p = 0.01, N = 10), with no such relationship seen in AD.
      • Rowe C.C.
      • Ng S.
      • Ackermann U.
      • et al.
      Imaging beta-amyloid burden in aging and dementia.
      Maetzler et al.
      • Maetzler W.
      • Liepelt I.
      • Reimold M.
      • et al.
      Cortical PIB binding in Lewy body disease is associated with Alzheimer-like characteristics.
      found that in a combined DLB and PDD group, Aβ-positive patients had an older age at onset of parkinsonism and dementia and had lower MMSE scores. The authors suggested that this may be an effect of increasing Aβ with increasing age, or that cortical Aβ deposition is associated with different disease mechanisms resulting in an older age of onset and more rapid clinical progression.
      In a small group of treatment-naive patients, Graff-Radford et al.
      • Graff-Radford J.
      • Boeve B.F.
      • Pedraza O.
      • et al.
      Imaging and acetylcholinesterase inhibitor response in dementia with Lewy bodies.
      found that after treatment with acetylcholinesterase inhibitors Aβ-positive patients (N = 3) tended to remain stable or decline, whereas Aβ-negative patients (N = 4) tended to remain stable or improve.

      Relationship with genetics, imaging findings, and other biomarkers

      An early study found the apolipoprotein E4 (ApoE4) genotype was associated with increased 11C-PiB binding across groups (including relatively large groups of AD and controls) but not within diagnostic groups.
      • Rowe C.C.
      • Ng S.
      • Ackermann U.
      • et al.
      Imaging beta-amyloid burden in aging and dementia.
      Similarly, in a large study, Gomperts et al.
      • Gomperts S.N.
      • Locascio J.J.
      • Marquie M.
      • et al.
      Brain amyloid and cognition in Lewy body diseases.
      found that ApoE4 genotype and 11C-PiB binding were correlated across the entire cohort (DLB, PDD, PD-MCI, PD, controls; r = 0.49, p <0.0001). In a study involving DLB, PDD, and PD subjects, the Aβ-positive group (all of whom had dementia) were found to have increased rates of the ApoE4 allele and lower cerebrospinal fluid (CSF) Aβ42 concentrations compared with Aβ-negative patients.
      • Maetzler W.
      • Liepelt I.
      • Reimold M.
      • et al.
      Cortical PIB binding in Lewy body disease is associated with Alzheimer-like characteristics.
      These results are consistent with findings in AD subjects, those with MCI, and apparently healthy older controls that the ApoE4 genotype is robustly associated with increased Aβ binding.
      • Fleisher A.S.
      • Chen K.
      • Liu X.
      • et al.
      Apolipoprotein E epsilon4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease.
      • Drzezga A.
      • Grimmer T.
      • Henriksen G.
      • et al.
      Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease.
      In a recent study, Shimada et al.

      Shimada H, Shinotoh H, Hirano S, et al: Beta-amyloid in Lewy body disease is related to Alzheimer's disease-like atrophy. Mov Disord 2013; 28:169–175

      examined the association between 11C-PiB binding and cortical atrophy in a combined PDD/DLB group compared with AD and healthy controls. They found that 6 of 15 PDD/DLB patients were 11C-PiB–positive. Compared with 11C-PiB–negative controls (11C-PiB–positive controls were excluded), the 11C-PiB–positive PDD/DLB group demonstrated significant cortical atrophy, particularly in temporal and parietal areas, whereas the 11C-PiB–negative group did not. Using volume of interest analysis, the 11C-PiB–positive PDD/DLB group had lower parahippocampal gray matter volume than 11C-PiB–negative PDD/DLB subjects. There were no differences between the two groups in cognitive tests. Atrophy was not correlated with Aβ ligand binding in any group. The authors commented that Aβ deposition in PDD/DLB appeared to be associated with cortical atrophy in a pattern similar to that seen in AD, though the level of atrophy itself was not correlated with amyloid load and likely due to downstream effects.
      Three studies have compared amyloid imaging scans with 18F-FDG PET in Lewy body disorders.
      • Kantarci K.
      • Lowe V.J.
      • Boeve B.F.
      • et al.
      Multimodality imaging characteristics of dementia with Lewy bodies.
      • Claassen D.O.
      • Lowe V.J.
      • Peller P.J.
      • et al.
      Amyloid and glucose imaging in dementia with Lewy bodies and multiple systems atrophy.
      • Jokinen P.
      • Scheinin N.
      • Aalto S.
      • et al.
      [(11)C]PIB-, [(18)F]FDG-PET and MRI imaging in patients with Parkinson's disease with and without dementia.
      Two studies in DLB and PDD reported brain hypometabolism (in areas such as the occipital and posterior parietotemporal lobes) in the absence of Aβ deposition and suggested that the two processes do not appear directly related, similar to the apparent dissociation between structural MR measures of atrophy and PET hypometabolism in DLB.
      • Sinha N.
      • Firbank M.
      • O'Brien J.T.
      Biomarkers in dementia with Lewy bodies: a review.
      One smaller study (N = 3) found corresponding hypometabolism and amyloid deposition in several cortical areas.
      • Claassen D.O.
      • Lowe V.J.
      • Peller P.J.
      • et al.
      Amyloid and glucose imaging in dementia with Lewy bodies and multiple systems atrophy.

      Diagnostic utility

      Some studies have investigated the diagnostic value of amyloid imaging in conjunction with other imaging methods. Burke et al.
      • Burke J.F.
      • Albin R.L.
      • Koeppe R.A.
      • et al.
      Assessment of mild dementia with amyloid and dopamine terminal positron emission tomography.
      used qualitative assessment of Aβ and dopamine transporter PET imaging in combination to diagnose patients with AD, DLB, or frontotemporal dementia, and compared concordance with clinical diagnosis. The overall agreement was poor (κ = 0.39; 95% confidence interval: 0.18–0.61). The best agreement was for the diagnosis of DLB, and subjects were classified as such based solely on positive dopamine transporter PET results.
      In a study of 21 DLB and 21 AD patients, a combination of hippocampal volume on structural MRI, cortical Aβ ligand binding, and occipital lobe hypometabolism on PET could differentiate between AD and DLB with an accuracy of 98%, with each imaging technique contributing significantly to the model used.
      • Kantarci K.
      • Lowe V.J.
      • Boeve B.F.
      • et al.
      Multimodality imaging characteristics of dementia with Lewy bodies.
      Amyloid PET alone had an area under the receiver operating curve of 0.89 (p <0.001).
      Reviewing data from studies that provided data in the form of dot-plots,
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      • Villemagne V.L.
      • Ong K.
      • Mulligan R.S.
      • et al.
      Amyloid Imaging with F-18-Florbetaben in Alzheimer Disease and Other Dementias.
      • Rowe C.C.
      • Ng S.
      • Ackermann U.
      • et al.
      Imaging beta-amyloid burden in aging and dementia.
      it is clear that even using post hoc ideal thresholds to differentiate between AD and DLB based on amyloid ligand binding, specificity remains poor (50%–71%; as a proportion of DLB cases have raised cortical amyloid), though sensitivity for AD can be up to 97% (as low amyloid in AD is rare).
      Ossenkoppele et al.

      Ossenkoppele R, Prins ND, Pijnenburg YA, et al: Impact of molecular imaging on the diagnostic process in a memory clinic. Alzheimers Dement 2013; 9:414–421

      performed 11C-PiB and 18F-FDG PET scans on 154 patients at a specialist memory clinic. Clinicians were asked to make a diagnosis following clinical assessment but before the scans, and to express their certainty in the diagnosis. Following the scan results the diagnosis was reassessed. Clinical diagnosis changed in 23% of cases. Clinicians reported that 11C-PiB PET contributed to the diagnosis in 86% of patients, mostly as a test that may rule out AD.

      Reports of Postmortem Examination After Amyloid PET Imaging

      The first postmortem report of a patient with DLB who had had an amyloid PET scan was by Bacskai et al.
      • Bacskai B.J.
      • Frosch M.P.
      • Freeman S.H.
      • et al.
      Molecular imaging with Pittsburgh Compound B confirmed at autopsy: a case report.
      They found that amyloid imaging findings corresponded to postmortem Aβ levels in brain homogenates measured using enzyme-linked immunosorbent assays. Much of the Aβ burden on imaging was due to cerebral Aβ angiopathy.
      Burack et al.
      • Burack M.A.
      • Hartlein J.
      • Flores H.P.
      • et al.
      In vivo amyloid imaging in autopsy-confirmed Parkinson disease with dementia.
      examined three patients with PDD, two of whom had extensive cortical 11C-PiB uptake in PET scans before death. Both were found to have abnormal levels of cortical Aβ (predominantly diffuse plaques) post mortem. All cortical areas with PET mean cortical binding potential greater than 0.2 had severe plaque burden post mortem. The case with no raised Aβ binding had minimal Aβ plaques but abundant cortical Lewy bodies, suggesting there is no significant binding of 11C-PiB to LBs during amyloid PET scans.
      Kantarci et al.
      • Kantarci K.
      • Lowe V.J.
      • Boeve B.F.
      • et al.
      Multimodality imaging characteristics of dementia with Lewy bodies.
      reported three cases of DLB with antemortem amyloid imaging. One had raised cortical 11C-PiB binding (11C-PiB retention ratio >1.6) and two had borderline binding (11C-PiB retention ratio: 1.4–1.6). The case with raised 11C-PiB had sparse neuritic plaques but frequent diffuse plaques. The two borderline cases had sparse or moderate neuritic plaques (the level of diffuse plaques was not mentioned).
      The case with raised 11C-PiB underwent quantitative comparison of amyloid deposition measured by 11C-PIB PET and postmortem image analysis of immunostains of corresponding regions.
      • Kantarci K.
      • Yang C.
      • Schneider J.A.
      • et al.
      Ante mortem amyloid imaging and beta-amyloid pathology in a case with dementia with Lewy bodies.
      There was a strong correlation between 11C-PiB retention (18 months antemortem) and postmortem Aβ density in the 17 regions of interest analyzed (r = 0.899; p <0.0001). Lewy body and tau density did not correlate with 11C-PiB retention.
      Ikonomovic et al.
      • Ikonomovic M.D.
      • Abrahamson E.E.
      • Price J.C.
      • et al.
      Early AD pathology in a C-11 PiB-negative case: a PiB-amyloid imaging, biochemical, and immunohistochemical study.
      examined a case of probable DLB with a negative 11C-PiB PET scan. Although postmortem examination did identify Aβ plaques, they were infrequent and primarily diffuse rather than neuritic. The authors commented that the level of amyloid deposition necessary to elicit a positive 11C-PiB PET scan is not yet clear. Postmortem Aβ42 concentration in brain homogenates correlated with 11C-PiB retention in the antemortem PET scan (r = 0.72, p = 0.009), corroborating the finding of Kantarci et al.
      • Kantarci K.
      • Lowe V.J.
      • Boeve B.F.
      • et al.
      Multimodality imaging characteristics of dementia with Lewy bodies.

      Conclusions

      Differences Between Diagnostic Groups

      In summary, all Lewy body disorders are generally associated with lower mean cortical Aβ ligand binding than AD. DLB is usually associated with higher mean cortical Aβ binding than PDD, PD, or controls. There are no significant differences between PDD, PD, and controls. When Aβ is present, the pattern of deposition in LB disorders is similar to that seen in AD, with deposition in frontal, parietal, and cingulate areas, along with the striatum. Only one study used an 18F-labeled tracer (Florbetaben),
      • Villemagne V.L.
      • Ong K.
      • Mulligan R.S.
      • et al.
      Amyloid Imaging with F-18-Florbetaben in Alzheimer Disease and Other Dementias.
      all other studies used 11C-PiB. The pattern of cortical binding with 18F-Florbetaben was almost identical to that of 11C-PiB, though to a slightly lesser degree.
      • Villemagne V.L.
      • Ong K.
      • Mulligan R.S.
      • et al.
      Amyloid Imaging with F-18-Florbetaben in Alzheimer Disease and Other Dementias.
      Some differences between diagnostic groups only become evident when subjects are classified as Aβ-positive or Aβ-negative based on a defined threshold. In most studies directly comparing rates of Aβ-positive subjects in each diagnostic group (Table 2), AD had higher rates than DLB, which in turn had higher rates than PDD, which had higher rates than PD or controls. Between PD and controls there was more variability, with controls having higher rates of Aβ-positive subjects in three of five studies in which they were directly compared. From these findings we can conclude that although Aβ deposition in itself is neither necessary nor sufficient for the development of dementia in LB disorders, the presence of Aβ is more common in those with dementia, and relatively rare in those without dementia. These findings mirror results from postmortem studies that have found greater Aβ deposition in DLB than PDD or PD,
      • Ballard C.
      • Ziabreva I.
      • Perry R.
      • et al.
      Differences in neuropathologic characteristics across the Lewy body dementia spectrum.
      • Fujishiro H.
      • Iseki E.
      • Higashi S.
      • et al.
      Distribution of cerebral amyloid deposition and its relevance to clinical phenotype in Lewy body dementia.
      • Harding A.J.
      • Halliday G.M.
      Cortical Lewy body pathology in the diagnosis of dementia.
      • Jellinger K.A.
      • Attems J.
      Prevalence and impact of vascular and Alzheimer pathologies in Lewy body disease.
      and higher deposition in PDD than PD.
      • Harding A.J.
      • Halliday G.M.
      Cortical Lewy body pathology in the diagnosis of dementia.
      • Compta Y.
      • Parkkinen L.
      • O'Sullivan S.S.
      • et al.
      Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important?.
      • Irwin D.J.
      • White M.T.
      • Toledo J.B.
      • et al.
      Neuropathologic substrates of Parkinson disease dementia.
      High levels of cortical Aβ are unusual in PD. Petrou et al.
      • Petrou M.
      • Bohnen N.I.
      • Muller M.L.
      • et al.
      Abeta-amyloid deposition in patients with Parkinson disease at risk for development of dementia.
      found that most of the small number of patients with Aβ-positive PET scans in a PD cohort identified for being at risk of dementia actually, on closer examination, already had dementia. Similarly, in a postmortem study of 129 cases of PD, 17 of 20 of patients that had Aβ plaque pathology rated CERAD
      • Mirra S.S.
      • Heyman A.
      • McKeel D.
      • et al.
      The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease.
      grade B or C had dementia (85% versus 54% in the overall group).
      • Kempster P.A.
      • Williams D.R.
      • Selikhova M.
      • et al.
      Patterns of levodopa response in Parkinson's disease: a clinico-pathological study.
      In another neuropathological study of 200 patients with an initial diagnosis of PD, higher CERAD scores were found almost exclusively in patients who developed dementia (CERAD scores PD: B = 3%, C = 0%; PDD: B = 51%, C = 33%).
      • Jellinger K.A.
      • Seppi K.
      • Wenning G.K.
      • et al.
      Impact of coexistent Alzheimer pathology on the natural history of Parkinson's disease.
      Diffuse neocortical or limbic Lewy body pathology is generally seen as the main substrate of dementia in LB disorders.
      • Emre M.
      • Aarsland D.
      • Brown R.
      • et al.
      Clinical diagnostic criteria for dementia associated with Parkinson's disease.
      • Irwin D.J.
      • White M.T.
      • Toledo J.B.
      • et al.
      Neuropathologic substrates of Parkinson disease dementia.
      • Aarsland D.
      • Perry R.
      • Brown A.
      • et al.
      Neuropathology of dementia in Parkinson's disease: a prospective, community-based study.
      These findings suggest that the presence of Aβ confers a higher risk for the development of dementia in LB disorders. A possible explanation for this is that the combination of cortical Aβ and Lewy body pathology may have synergistic effects. Some postmortem studies have found that increased Aβ is associated with increased α-synuclein levels in the brain in Lewy body disorders and AD,
      • Pletnikova O.
      • West N.
      • Lee M.K.
      • et al.
      Abeta deposition is associated with enhanced cortical alpha-synuclein lesions in Lewy body diseases.
      • Compta Y.
      • Parkkinen L.
      • O'Sullivan S.S.
      • et al.
      Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important?.
      • Lashley T.
      • Holton J.L.
      • Gray E.
      • et al.
      Cortical alpha-synuclein load is associated with amyloid-beta plaque burden in a subset of Parkinson's disease patients.
      although other studies have contradicted this.
      • Aarsland D.
      • Perry R.
      • Brown A.
      • et al.
      Neuropathology of dementia in Parkinson's disease: a prospective, community-based study.
      • Ballard C.G.
      • Jacoby R.
      • Del Ser T.
      • et al.
      Neuropathological substrates of psychiatric symptoms in prospectively studied patients with autopsy-confirmed dementia with lewy bodies.
      Interestingly, Aβ promotes the formation of α-synuclein oligomers and polymers in vitro.
      • Masliah E.
      • Rockenstein E.
      • Veinbergs I.
      • et al.
      Beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease.
      Experiments in transgenic mice expressing human Aβ, tau, and α-synuclein peptides have shown that the presence of Aβ increases the formation of α-synuclein neuronal inclusions
      • Masliah E.
      • Rockenstein E.
      • Veinbergs I.
      • et al.
      Beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease.
      and α-synuclein increases the deposition of both Aβ and tau.
      • Clinton L.K.
      • Blurton-Jones M.
      • Myczek K.
      • et al.
      Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline.
      Thus, in LB disorders, the presence of significant Aβ may lead to a synergistic interaction with α-synuclein, resulting in widespread deposition of α-synuclein and Aβ, leading to cognitive impairment. This hypothesis may help explain the infrequency of significant Aβ deposition in PD without cognitive impairment and the increased rates of Aβ seen in DLB compared with PDD, as DLB by definition demonstrates dementia (an indicator of widespread neurodegeneration) earlier in the disorder. The apparent synergistic interaction between Aβ and α-synuclein is a possible target for therapeutic intervention, given our ability to identify the subset of Lewy body disease sufferers with Aβ deposition using PET imaging.

      Relationship of Aβ to Clinical Picture

      In imaging studies cognitive impairment has correlated positively with Aβ ligand binding across diagnostic groups.
      • Gomperts S.N.
      • Rentz D.M.
      • Moran E.
      • et al.
      Imaging amyloid deposition in Lewy body diseases.
      • Villemagne V.L.
      • Ong K.
      • Mulligan R.S.
      • et al.
      Amyloid Imaging with F-18-Florbetaben in Alzheimer Disease and Other Dementias.
      This may simply reflect that Aβ burden is high in AD and DLB and low in PD and controls. More interestingly, Aβ binding may be correlated with cognitive impairment in Lewy body dementia only–groups
      • Foster E.R.
      • Campbell M.C.
      • Burack M.A.
      • et al.
      Amyloid imaging of Lewy body-associated disorders.
      • Maetzler W.
      • Liepelt I.
      • Reimold M.
      • et al.
      Cortical PIB binding in Lewy body disease is associated with Alzheimer-like characteristics.
      and may predict cognitive decline in PD and PD-MCI.
      • Gomperts S.N.
      • Locascio J.J.
      • Rentz D.
      • et al.
      Amyloid is linked to cognitive decline in patients with Parkinson disease without dementia.
      Some pathological studies support these findings. Patients with a combination of DLB and AD pathology post mortem have been found to have had worse cognitive function,
      • Nelson P.T.
      • Kryscio R.J.
      • Jicha G.A.
      • et al.
      Relative preservation of MMSE scores in autopsy-proven dementia with Lewy bodies.
      more severe dementia,
      • Serby M.
      • Brickman A.M.
      • Haroutunian V.
      • et al.
      Cognitive burden and excess Lewy-body pathology in the Lewy-body variant of Alzheimer disease.
      and a faster rate of cognitive decline
      • Kraybill M.L.
      • Larson E.B.
      • Tsuang D.W.
      • et al.
      Cognitive differences in dementia patients with autopsy-verified AD, Lewy body pathology, or both.
      than those with “pure” DLB pathology. A correlation between cognitive impairment and Aβ deposition in PD and PDD groups has been found,
      • Harding A.J.
      • Halliday G.M.
      Cortical Lewy body pathology in the diagnosis of dementia.
      • Compta Y.
      • Parkkinen L.
      • O'Sullivan S.S.
      • et al.
      Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important?.
      • Mattila P.M.
      • Rinne J.O.
      • Helenius H.
      • et al.
      Alpha-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson's disease.
      although this link did not survive regression modelling in some studies.
      • Mattila P.M.
      • Rinne J.O.
      • Helenius H.
      • et al.
      Alpha-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson's disease.
      Conversely, other studies have found no correlation of MMSE with CERAD score in PD with or without cognitive impairment,
      • Aarsland D.
      • Perry R.
      • Brown A.
      • et al.
      Neuropathology of dementia in Parkinson's disease: a prospective, community-based study.
      • Braak H.
      • Rub U.
      • Jansen Steur E.N.
      • et al.
      Cognitive status correlates with neuropathologic stage in Parkinson disease.
      and AD pathology in PDD has been found not to affect performance on MMSE or other neuropsychological tests.
      • Sabbagh M.N.
      • Adler C.H.
      • Lahti T.J.
      • et al.
      Parkinson disease with dementia: comparing patients with and without Alzheimer pathology.
      Imaging studies have found suggestive links between increased Aβ ligand binding and older onset of motor impairment and dementia,
      • Maetzler W.
      • Liepelt I.
      • Reimold M.
      • et al.
      Cortical PIB binding in Lewy body disease is associated with Alzheimer-like characteristics.
      and a shorter interval between the onset of motor impairment and cognitive impairment.
      • Rowe C.C.
      • Ng S.
      • Ackermann U.
      • et al.
      Imaging beta-amyloid burden in aging and dementia.
      There have been various, often contradictory, pathological findings about the association of Aβ deposition with disease onset and progression in LB disorders.
      Increased Aβ burden post mortem has been associated with older age of onset and shorter survival in DLB, PD, and PDD;
      • Jellinger K.A.
      • Seppi K.
      • Wenning G.K.
      • et al.
      Impact of coexistent Alzheimer pathology on the natural history of Parkinson's disease.
      and shorter duration of parkinsonism prior to the onset of dementia in PDD and DLB.
      • Ballard C.
      • Ziabreva I.
      • Perry R.
      • et al.
      Differences in neuropathologic characteristics across the Lewy body dementia spectrum.
      • Fujishiro H.
      • Iseki E.
      • Higashi S.
      • et al.
      Distribution of cerebral amyloid deposition and its relevance to clinical phenotype in Lewy body dementia.
      • Selikhova M.
      • Williams D.R.
      • Kempster P.A.
      • et al.
      A clinico-pathological study of subtypes in Parkinson's disease.
      • Compta Y.
      • Parkkinen L.
      • O'Sullivan S.S.
      • et al.
      Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important?.
      • Ballard C.G.
      • Jacoby R.
      • Del Ser T.
      • et al.
      Neuropathological substrates of psychiatric symptoms in prospectively studied patients with autopsy-confirmed dementia with lewy bodies.
      Other studies found no correlation between Aβ burden age of onset, disease duration, and age of death in DLB
      • Nelson P.T.
      • Kryscio R.J.
      • Jicha G.A.
      • et al.
      Relative preservation of MMSE scores in autopsy-proven dementia with Lewy bodies.
      • Ballard C.G.
      • Jacoby R.
      • Del Ser T.
      • et al.
      Neuropathological substrates of psychiatric symptoms in prospectively studied patients with autopsy-confirmed dementia with lewy bodies.
      or PD;56 rate of decline in PD or PDD
      • Aarsland D.
      • Perry R.
      • Brown A.
      • et al.
      Neuropathology of dementia in Parkinson's disease: a prospective, community-based study.
      ; or the interval between motor and dementia symptoms in PDD.
      • Irwin D.J.
      • White M.T.
      • Toledo J.B.
      • et al.
      Neuropathologic substrates of Parkinson disease dementia.
      Some even found increased Aβ to be associated with longer disease duration in PD, although with higher dementia scores.
      • Mattila P.M.
      • Rinne J.O.
      • Helenius H.
      • et al.
      Alpha-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson's disease.
      A large epidemiological study
      • Aarsland D.
      • Kvaloy J.T.
      • Andersen K.
      • et al.
      The effect of age of onset of PD on risk of dementia.
      found that the occurrence of dementia in PD was a function of age, and age of onset had no effect above this. Thus, in some studies the shorter duration of parkinsonism before dementia observed in Aβ positive patients could simply be a function of their older age.
      • Fujishiro H.
      • Iseki E.
      • Higashi S.
      • et al.
      Distribution of cerebral amyloid deposition and its relevance to clinical phenotype in Lewy body dementia.
      • Compta Y.
      • Parkkinen L.
      • O'Sullivan S.S.
      • et al.
      Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important?.
      Findings from amyloid imaging studies can drive hypotheses that should then be tested in other imaging studies as well as pathological studies. Similarly, pathological findings (from which most of our current knowledge of the Aβ in LB disorders derives) will drive hypotheses in future imaging studies. Some other positive findings from these early imaging studies that should be tested in future studies include the links between striatal Aβ and parkinsonism; parietal/posterior cingulate Aβ and visuoperceptual ability; and Aβ ligand binding, ApoE genotype, and CSF Aβ42. Further studies are also needed to corroborate the finding that the other core symptoms of DLB, visual hallucinations and fluctuating cognition, are not related to Aβ deposition.
      Based on current data it is not possible to make any firm conclusions on the influence of Aβ pathology on disease progression and clinical phenotype in Lewy body disorders. There are a few reasons for this. Aβ imaging studies have thus far, with two exceptions, been cross-sectional rather than longitudinal. Studies vary in image acquisition, processing, and analysis; clinical and imaging outcome measures used and cutoff points for Aβ-positive and Aβ-negative cases; recruitment source (i.e., movement disorder or memory clinics); entry criteria for subjects; and processing of results (e.g., the removal of control/PDD subjects with raised amyloid from analysis
      • Edison P.
      • Rowe C.C.
      • Rinne J.O.
      • et al.
      Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography.
      • Maetzler W.
      • Reimold M.
      • Liepelt I.
      • et al.
      [11C]PIB binding in Parkinson's disease dementia.

      Shimada H, Shinotoh H, Hirano S, et al: Beta-amyloid in Lewy body disease is related to Alzheimer's disease-like atrophy. Mov Disord 2013; 28:169–175

      ). Few studies have tested the same hypotheses using comparable outcome measures. Many studies also suffered from low sample sizes, and suboptimal measures such as the MMSE, which may not be sensitive to cognitive changes in LB disorders. These problems, and a tendency in some studies to report the results of statistical tests without summary data, prevented any quantitative meta-analysis of the results. Large-scale, prospective studies are needed to properly investigate the effect of Aβ burden on the onset, progression, severity, and character of symptoms in LB disorders.
      Neuropathological studies suffer from similar inconsistencies (e.g., in the use of grading rather than fully quantitative measures to assess brain pathology). Comparison between imaging and pathological studies is difficult as amyloid PET measures both diffuse and neuritic plaques, as well as amyloid angiopathy, whereas most pathological studies focus solely on neuritic plaques. Although 11C-PiB has higher affinity for neuritic plaques, diffuse plaques account for most of the in vivo binding in LB disorders.
      • Burack M.A.
      • Hartlein J.
      • Flores H.P.
      • et al.
      In vivo amyloid imaging in autopsy-confirmed Parkinson disease with dementia.
      • Kantarci K.
      • Yang C.
      • Schneider J.A.
      • et al.
      Ante mortem amyloid imaging and beta-amyloid pathology in a case with dementia with Lewy bodies.
      Some authors have questioned the ability of PET amyloid imaging to adequately quantify amyloid burden, highlighting problems with current PET amyloid imaging technology including partial volume effects and nonspecific binding of amyloid radioligands.
      • Moghbel M.C.
      • Saboury B.
      • Basu S.
      • et al.
      Amyloid-beta imaging with PET in Alzheimer's disease: is it feasible with current radiotracers and technologies?.
      PET imaging has a relatively low resolution compared with MRI. This results in a relatively large voxel size. Given the thinness of the cerebral cortex, partial volume effects (where a voxel contains signal from both gray and white matter, or gray matter and CSF, for instance) are possible.
      • Moghbel M.C.
      • Saboury B.
      • Basu S.
      • et al.
      Amyloid-beta imaging with PET in Alzheimer's disease: is it feasible with current radiotracers and technologies?.
      This is further complicated by the presence of significant cortical atrophy in a proportion of subjects with cognitive impairment. Although this problem is by no means unique to PET amyloid imaging, it does raise doubts about the ability of PET imaging to accurately quantify amyloid burden in dementia and highlights the importance of the use of correction measures for partial volume effects.
      • Villemagne V.L.
      • Klunk W.E.
      • Mathis C.A.
      • et al.
      A beta imaging: feasible, pertinent, and vital to progress in Alzheimer's disease.
      Few of the studies reviewed here used such correction measures (Table 1).
      Amyloid radioligands, particularly 18F-labeled ligands, have high nonspecific white-matter binding.
      • Rowe C.C.
      • Villemagne V.L.
      Brain amyloid imaging.
      Studies comparing PiB binding (in vitro and in vivo) with amyloid burden measured by immunohistochemistry have demonstrated that PiB does not give a direct quantitative measure of cortical amyloid burden.
      • Bacskai B.J.
      • Frosch M.P.
      • Freeman S.H.
      • et al.
      Molecular imaging with Pittsburgh Compound B confirmed at autopsy: a case report.
      • Svedberg M.M.
      • Hall H.
      • Hellstrom-Lindahl E.
      • et al.
      [(11)C]PIB-amyloid binding and levels of Abeta40 and Abeta42 in postmortem brain tissue from Alzheimer patients.
      Similarly, a study comparing in vivo PiB binding with amyloid burden post mortem found cases where the precuneus was observed to have the highest PiB retention, despite other brain areas having markedly greater amyloid burden quantified by stereological assessment.
      • Driscoll I.
      • Troncoso J.C.
      • Rudow G.
      • et al.
      Correspondence between in vivo (11)C-PiB-PET amyloid imaging and postmortem, region-matched assessment of plaques.
      It should be noted that, despite this, there was a strong correlation between 11C-PiB binding and postmortem amyloid burden in the precuneus, anterior cingulate, and posterior cingulate, though not the hippocampus or orbitofrontal cortex.
      • Driscoll I.
      • Troncoso J.C.
      • Rudow G.
      • et al.
      Correspondence between in vivo (11)C-PiB-PET amyloid imaging and postmortem, region-matched assessment of plaques.
      Thus, although ligand retention and amyloid burden are correlated in different brain areas within one subject
      • Kantarci K.
      • Yang C.
      • Schneider J.A.
      • et al.
      Ante mortem amyloid imaging and beta-amyloid pathology in a case with dementia with Lewy bodies.
      and between subjects,
      • Clark C.M.
      • Schneider J.A.
      • Bedell B.J.
      • et al.
      Use of florbetapir-PET for imaging beta-amyloid pathology.
      • Driscoll I.
      • Troncoso J.C.
      • Rudow G.
      • et al.
      Correspondence between in vivo (11)C-PiB-PET amyloid imaging and postmortem, region-matched assessment of plaques.
      amyloid PET cannot be said to precisely quantify amyloid burden in each particular brain area. These issues should be borne in mind when interpreting and discussing amyloid PET findings.

      Clinical Use and Diagnostic Utility

      The large variability in Aβ binding found in DLB and PDD limits the use of Aβ imaging in isolation in the diagnosis of dementia. It may improve accuracy, however, when used in conjunction with other biomarkers such as structural MRI and FDG-PET.
      • Kantarci K.
      • Lowe V.J.
      • Boeve B.F.
      • et al.
      Multimodality imaging characteristics of dementia with Lewy bodies.
      Aβ imaging has negative predictive value in the diagnosis of AD, positive predictive value for the development of dementia in MCI, and clinicians find it of use in the diagnosis of dementia, particularly where diagnostic confidence is low.

      Ossenkoppele R, Prins ND, Pijnenburg YA, et al: Impact of molecular imaging on the diagnostic process in a memory clinic. Alzheimers Dement 2013; 9:414–421

      • Herholz K.
      • Ebmeier K.
      Clinical amyloid imaging in Alzheimer's disease.
      Given that Aβ deposition is uncommon in PD compared with PDD, amyloid imaging in PD may be useful to identify cognitively normal or subsyndromal patients who will later go on to develop dementia. This test may be expected to have a high positive predictive value but a low sensitivity, given the frequent occurrence of PDD in the absence of significant Aβ pathology. In one study, two out of three PD subjects with a high amyloid ligand binding later developed MCI.
      • Gomperts S.N.
      • Locascio J.J.
      • Rentz D.
      • et al.
      Amyloid is linked to cognitive decline in patients with Parkinson disease without dementia.
      Further prospective studies are required to investigate this.
      Neuropathological studies have found that NFT pathology in DLB may be associated with a clinical picture more similar to AD than classical DLB.
      • Ballard C.G.
      • Jacoby R.
      • Del Ser T.
      • et al.
      Neuropathological substrates of psychiatric symptoms in prospectively studied patients with autopsy-confirmed dementia with lewy bodies.
      • Fujishiro H.
      • Ferman T.J.
      • Boeve B.F.
      • et al.
      Validation of the neuropathologic criteria of the third consortium for dementia with Lewy bodies for prospectively diagnosed cases.
      The degree to which high Aβ binding is also associated with a less classical DLB clinical phenotype is of interest; such patients may have a different prognosis, different levels of neuroleptic sensitivity, and a different response to treatment.
      There is a relative paucity of NFT pathology in LB disorders,
      • Braak H.
      • Rub U.
      • Jansen Steur E.N.
      • et al.
      Cognitive status correlates with neuropathologic stage in Parkinson disease.
      but when present it is a reliable correlate of dementia.
      • Irwin D.J.
      • White M.T.
      • Toledo J.B.
      • et al.
      Neuropathologic substrates of Parkinson disease dementia.
      • Jellinger K.A.
      • Seppi K.
      • Wenning G.K.
      • et al.
      Impact of coexistent Alzheimer pathology on the natural history of Parkinson's disease.
      Although no imaging ligands for tau are yet available, there are imaging correlates of tau pathology. Brain atrophy on MRI, particularly in the medial temporal lobe, has been found to be associated with postmortem tau pathology, measured quantitatively with tau antibody and image analysis or semiquantitatively using Braak NFT staging.
      • Burton E.J.
      • Barber R.
      • Mukaetova-Ladinska E.B.
      • et al.
      Medial temporal lobe atrophy on MRI differentiates Alzheimer's disease from dementia with Lewy bodies and vascular cognitive impairment: a prospective study with pathological verification of diagnosis.
      • Whitwell J.L.
      • Josephs K.A.
      • Murray M.E.
      • et al.
      MRI correlates of neurofibrillary tangle pathology at autopsy: a voxel-based morphometry study.
      • Braak H.
      • Braak E.
      Neuropathological stageing of Alzheimer-related changes.
      A recent study has found brain atrophy in amyloid-positive, but not amyloid-negative, PDD/DLB subjects,

      Shimada H, Shinotoh H, Hirano S, et al: Beta-amyloid in Lewy body disease is related to Alzheimer's disease-like atrophy. Mov Disord 2013; 28:169–175

      despite this, atrophy was not correlated with PiB binding. This may be because atrophy is the result of downstream effects, either of tau, α-synuclein, a combination of both, or another factor. A combination of amyloid imaging and MRI measures of atrophy (as a surrogate measure of tau pathology) may be important in any study wishing to investigate the influence of AD pathology in LB disorders.
      To conclude, amyloid imaging studies have demonstrated that significant Aβ deposition is present in a proportion of DLB and PDD patients. Significant Aβ deposition appears to be relatively rare in PD. Dementia often occurs in the absence of Aβ, but there is some evidence that amyloid may be related to the onset or progression of cognitive symptoms in these disorders, though current results are not conclusive. Large scale, prospective amyloid imaging studies may resolve some of these unanswered questions and clarify the importance of Aβ in LB disorders.
      This work was supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Unit based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.
      John O'Brien has acted as a consultant or received honoraria from GE Healthcare, Bayer Healthcare, and Lilly, and has received a grant from Lilly for an investigator-initiated study. Alan Thomas has received grant funding from GE Healthcare for an investigator-initiated study. For the remaining author no conflicts of interest were declared.

      References

        • McKeith I.G.
        • Galasko D.
        • Kosaka K.
        • et al.
        Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop.
        Neurology. 1996; 47: 1113-1124
        • Stevens T.
        • Livingston G.
        • Kitchen G.
        • et al.
        Islington study of dementia subtypes in the community.
        Br J Psychiatry. 2002; 180: 270-276
        • Emre M.
        • Aarsland D.
        • Brown R.
        • et al.
        Clinical diagnostic criteria for dementia associated with Parkinson's disease.
        Mov Disord. 2007; 22 (quiz 1837): 1689-1707
        • McKeith I.G.
        • Dickson D.W.
        • Lowe J.
        • et al.
        Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.
        Neurology. 2005; 65: 1863-1872
        • McKeith I.
        Commentary: DLB and PDD: the same or different? Is there a debate?.
        Int Psychogeriatr. 2009; 21: 220-224
        • Kovari E.
        • Horvath J.
        • Bouras C.
        Neuropathology of Lewy body disorders.
        Brain Res Bull. 2009; 80: 203-210
        • Merdes A.R.
        • Hansen L.A.
        • Jeste D.V.
        • et al.
        Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies.
        Neurology. 2003; 60: 1586-1590
        • Weisman D.
        • Cho M.
        • Taylor C.
        • et al.
        In dementia with Lewy bodies, Braak stage determines phenotype, not Lewy body distribution.
        Neurology. 2007; 69: 356-359
        • Del Ser T.
        • Hachinski V.
        • Merskey H.
        • et al.
        Clinical and pathologic features of two groups of patients with dementia with Lewy bodies: effect of coexisting Alzheimer-type lesion load.
        Alzheimer Dis Assoc Disord. 2001; 15: 31-44
        • Nelson P.T.
        • Kryscio R.J.
        • Jicha G.A.
        • et al.
        Relative preservation of MMSE scores in autopsy-proven dementia with Lewy bodies.
        Neurology. 2009; 73: 1127-1133
        • Ballard C.
        • Ziabreva I.
        • Perry R.
        • et al.
        Differences in neuropathologic characteristics across the Lewy body dementia spectrum.
        Neurology. 2006; 67: 1931-1934
        • Fujishiro H.
        • Iseki E.
        • Higashi S.
        • et al.
        Distribution of cerebral amyloid deposition and its relevance to clinical phenotype in Lewy body dementia.
        Neurosci Lett. 2010; 486: 19-23
        • Selikhova M.
        • Williams D.R.
        • Kempster P.A.
        • et al.
        A clinico-pathological study of subtypes in Parkinson's disease.
        Brain. 2009; 132: 2947-2957
        • Aarsland D.
        • Ballard C.G.
        • Halliday G.
        Are Parkinson's disease with dementia and dementia with Lewy bodies the same entity?.
        J Geriatr Psychiatry Neurol. 2004; 17: 137-145
        • Jellinger K.A.
        • Seppi K.
        • Wenning G.K.
        Clinical and neuropathological correlates of Lewy body disease.
        Acta Neuropathol. 2003; 106 (author reply 190): 188-189
        • Pletnikova O.
        • West N.
        • Lee M.K.
        • et al.
        Abeta deposition is associated with enhanced cortical alpha-synuclein lesions in Lewy body diseases.
        Neurobiol Aging. 2005; 26: 1183-1192
        • Rowe C.C.
        • Villemagne V.L.
        Brain amyloid imaging.
        J Nucl Med. 2011; 52: 1733-1740
        • Sojkova J.
        • Driscoll I.
        • Iacono D.
        • et al.
        In vivo fibrillar beta-amyloid detected using [11C]PiB positron emission tomography and neuropathologic assessment in older adults.
        Arch Neurol. 2011; 68: 232-240
        • Clark C.M.
        • Schneider J.A.
        • Bedell B.J.
        • et al.
        Use of florbetapir-PET for imaging beta-amyloid pathology.
        JAMA. 2011; 305: 275-283
        • Ikonomovic M.D.
        • Klunk W.E.
        • Abrahamson E.E.
        • et al.
        Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease.
        Brain. 2008; 131: 1630-1645
        • Quigley H.
        • Colloby S.J.
        • O'Brien J.T.
        PET imaging of brain amyloid in dementia: a review.
        Int J Geriatr Psychiatry. 2011; 26: 991-999
        • Rosenberg P.B.
        • Wong D.F.
        • Edell S.L.
        • et al.
        Cognition and amyloid load in Alzheimer disease imaged with florbetapir F 18(AV-45) positron emission tomography.
        Am J Geriatr Psychiatry. 2013; 21: 272-278
        • Edison P.
        • Rowe C.C.
        • Rinne J.O.
        • et al.
        Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography.
        J Neurol Neurosurg Psychiatry. 2008; 79: 1331-1338
        • Gomperts S.N.
        • Rentz D.M.
        • Moran E.
        • et al.
        Imaging amyloid deposition in Lewy body diseases.
        Neurology. 2008; 71: 903-910
        • Gomperts S.N.
        • Locascio J.J.
        • Marquie M.
        • et al.
        Brain amyloid and cognition in Lewy body diseases.
        Mov Disord. 2012; 27: 965-973
        • Kantarci K.
        • Lowe V.J.
        • Boeve B.F.
        • et al.
        Multimodality imaging characteristics of dementia with Lewy bodies.
        Neurobiol Aging. 2012; 33: 2091-2105
        • Foster E.R.
        • Campbell M.C.
        • Burack M.A.
        • et al.
        Amyloid imaging of Lewy body-associated disorders.
        Mov Disord. 2010; 25: 2516-2523
        • Villemagne V.L.
        • Ong K.
        • Mulligan R.S.
        • et al.
        Amyloid Imaging with F-18-Florbetaben in Alzheimer Disease and Other Dementias.
        J Nucl Med. 2011; 52: 1210-1217
        • Claassen D.O.
        • Lowe V.J.
        • Peller P.J.
        • et al.
        Amyloid and glucose imaging in dementia with Lewy bodies and multiple systems atrophy.
        Parkinsonism Relat Disord. 2011; 17: 160-165
        • Rowe C.C.
        • Ng S.
        • Ackermann U.
        • et al.
        Imaging beta-amyloid burden in aging and dementia.
        Neurology. 2007; 68: 1718-1725
        • Maetzler W.
        • Reimold M.
        • Liepelt I.
        • et al.
        [11C]PIB binding in Parkinson's disease dementia.
        Neuroimage. 2008; 39: 1027-1033
        • Petrou M.
        • Bohnen N.I.
        • Muller M.L.
        • et al.
        Abeta-amyloid deposition in patients with Parkinson disease at risk for development of dementia.
        Neurology. 2012; 79: 1161-1167
        • Maetzler W.
        • Liepelt I.
        • Reimold M.
        • et al.
        Cortical PIB binding in Lewy body disease is associated with Alzheimer-like characteristics.
        Neurobiol Dis. 2009; 34: 107-112
      1. Shimada H, Shinotoh H, Hirano S, et al: Beta-amyloid in Lewy body disease is related to Alzheimer's disease-like atrophy. Mov Disord 2013; 28:169–175

        • Jokinen P.
        • Scheinin N.
        • Aalto S.
        • et al.
        [(11)C]PIB-, [(18)F]FDG-PET and MRI imaging in patients with Parkinson's disease with and without dementia.
        Parkinsonism Relat Disord. 2010; 16: 666-670
        • Johansson A.
        • Savitcheva I.
        • Forsberg A.
        • et al.
        [(11)C]-PIB imaging in patients with Parkinson's disease: preliminary results.
        Parkinsonism Relat Disord. 2008; 14: 345-347
        • Gomperts S.N.
        • Locascio J.J.
        • Rentz D.
        • et al.
        Amyloid is linked to cognitive decline in patients with Parkinson disease without dementia.
        Neurology. 2013; 80: 85-91
        • Graff-Radford J.
        • Boeve B.F.
        • Pedraza O.
        • et al.
        Imaging and acetylcholinesterase inhibitor response in dementia with Lewy bodies.
        Brain. 2012; 135: 2470-2477
        • Fleisher A.S.
        • Chen K.
        • Liu X.
        • et al.
        Apolipoprotein E epsilon4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease.
        Neurobiol Aging. 2013; 34: 1-12
        • Drzezga A.
        • Grimmer T.
        • Henriksen G.
        • et al.
        Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease.
        Neurology. 2009; 72: 1487-1494
        • Sinha N.
        • Firbank M.
        • O'Brien J.T.
        Biomarkers in dementia with Lewy bodies: a review.
        Int J Geriatr Psychiatry. 2012; 27: 443-453
        • Burke J.F.
        • Albin R.L.
        • Koeppe R.A.
        • et al.
        Assessment of mild dementia with amyloid and dopamine terminal positron emission tomography.
        Brain. 2011; 134: 1647-1657
      2. Ossenkoppele R, Prins ND, Pijnenburg YA, et al: Impact of molecular imaging on the diagnostic process in a memory clinic. Alzheimers Dement 2013; 9:414–421

        • Bacskai B.J.
        • Frosch M.P.
        • Freeman S.H.
        • et al.
        Molecular imaging with Pittsburgh Compound B confirmed at autopsy: a case report.
        Arch Neurol. 2007; 64: 431-434
        • Burack M.A.
        • Hartlein J.
        • Flores H.P.
        • et al.
        In vivo amyloid imaging in autopsy-confirmed Parkinson disease with dementia.
        Neurology. 2010; 74: 77-84
        • Kantarci K.
        • Yang C.
        • Schneider J.A.
        • et al.
        Ante mortem amyloid imaging and beta-amyloid pathology in a case with dementia with Lewy bodies.
        Neurobiol Aging. 2012; 33: 878-885
        • Ikonomovic M.D.
        • Abrahamson E.E.
        • Price J.C.
        • et al.
        Early AD pathology in a C-11 PiB-negative case: a PiB-amyloid imaging, biochemical, and immunohistochemical study.
        Acta Neuropathol. 2012; 123: 433-447
        • Harding A.J.
        • Halliday G.M.
        Cortical Lewy body pathology in the diagnosis of dementia.
        Acta Neuropathol. 2001; 102: 355-363
        • Jellinger K.A.
        • Attems J.
        Prevalence and impact of vascular and Alzheimer pathologies in Lewy body disease.
        Acta Neuropathol. 2008; 115: 427-436
        • Compta Y.
        • Parkkinen L.
        • O'Sullivan S.S.
        • et al.
        Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important?.
        Brain. 2011; 134: 1493-1505
        • Irwin D.J.
        • White M.T.
        • Toledo J.B.
        • et al.
        Neuropathologic substrates of Parkinson disease dementia.
        Ann Neurol. 2012; 72: 587-598
        • Mirra S.S.
        • Heyman A.
        • McKeel D.
        • et al.
        The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease.
        Neurology. 1991; 41: 479-486
        • Kempster P.A.
        • Williams D.R.
        • Selikhova M.
        • et al.
        Patterns of levodopa response in Parkinson's disease: a clinico-pathological study.
        Brain. 2007; 130: 2123-2128
        • Jellinger K.A.
        • Seppi K.
        • Wenning G.K.
        • et al.
        Impact of coexistent Alzheimer pathology on the natural history of Parkinson's disease.
        J Neural Transm. 2002; 109: 329-339
        • Aarsland D.
        • Perry R.
        • Brown A.
        • et al.
        Neuropathology of dementia in Parkinson's disease: a prospective, community-based study.
        Ann Neurol. 2005; 58: 773-776
        • Lashley T.
        • Holton J.L.
        • Gray E.
        • et al.
        Cortical alpha-synuclein load is associated with amyloid-beta plaque burden in a subset of Parkinson's disease patients.
        Acta Neuropathol. 2008; 115: 417-425
        • Ballard C.G.
        • Jacoby R.
        • Del Ser T.
        • et al.
        Neuropathological substrates of psychiatric symptoms in prospectively studied patients with autopsy-confirmed dementia with lewy bodies.
        Am J Psychiatry. 2004; 161: 843-849
        • Masliah E.
        • Rockenstein E.
        • Veinbergs I.
        • et al.
        Beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease.
        Proc Natl Acad Sci USA. 2001; 98: 12245-12250
        • Clinton L.K.
        • Blurton-Jones M.
        • Myczek K.
        • et al.
        Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline.
        J Neurosci. 2010; 30: 7281-7289
        • Serby M.
        • Brickman A.M.
        • Haroutunian V.
        • et al.
        Cognitive burden and excess Lewy-body pathology in the Lewy-body variant of Alzheimer disease.
        Am J Geriatr Psychiatry. 2003; 11: 371-374
        • Kraybill M.L.
        • Larson E.B.
        • Tsuang D.W.
        • et al.
        Cognitive differences in dementia patients with autopsy-verified AD, Lewy body pathology, or both.
        Neurology. 2005; 64: 2069-2073
        • Mattila P.M.
        • Rinne J.O.
        • Helenius H.
        • et al.
        Alpha-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson's disease.
        Acta Neuropathol. 2000; 100: 285-290
        • Braak H.
        • Rub U.
        • Jansen Steur E.N.
        • et al.
        Cognitive status correlates with neuropathologic stage in Parkinson disease.
        Neurology. 2005; 64: 1404-1410
        • Sabbagh M.N.
        • Adler C.H.
        • Lahti T.J.
        • et al.
        Parkinson disease with dementia: comparing patients with and without Alzheimer pathology.
        Alzheimer Dis Assoc Disord. 2009; 23: 295-297
        • Aarsland D.
        • Kvaloy J.T.
        • Andersen K.
        • et al.
        The effect of age of onset of PD on risk of dementia.
        J Neurol. 2007; 254: 38-45
        • Moghbel M.C.
        • Saboury B.
        • Basu S.
        • et al.
        Amyloid-beta imaging with PET in Alzheimer's disease: is it feasible with current radiotracers and technologies?.
        Eur J Nucl Med Mol Imaging. 2012; 39: 202-208
        • Villemagne V.L.
        • Klunk W.E.
        • Mathis C.A.
        • et al.
        A beta imaging: feasible, pertinent, and vital to progress in Alzheimer's disease.
        Eur J Nucl Med Mol Imaging. 2012; 39: 209-219
        • Svedberg M.M.
        • Hall H.
        • Hellstrom-Lindahl E.
        • et al.
        [(11)C]PIB-amyloid binding and levels of Abeta40 and Abeta42 in postmortem brain tissue from Alzheimer patients.
        Neurochem Int. 2009; 54: 347-357
        • Driscoll I.
        • Troncoso J.C.
        • Rudow G.
        • et al.
        Correspondence between in vivo (11)C-PiB-PET amyloid imaging and postmortem, region-matched assessment of plaques.
        Acta Neuropathol. 2012; 124: 823-831
        • Herholz K.
        • Ebmeier K.
        Clinical amyloid imaging in Alzheimer's disease.
        Lancet Neurol. 2011; 10: 667-670
        • Fujishiro H.
        • Ferman T.J.
        • Boeve B.F.
        • et al.
        Validation of the neuropathologic criteria of the third consortium for dementia with Lewy bodies for prospectively diagnosed cases.
        J Neuropathol Exp Neurol. 2008; 67: 649-656
        • Burton E.J.
        • Barber R.
        • Mukaetova-Ladinska E.B.
        • et al.
        Medial temporal lobe atrophy on MRI differentiates Alzheimer's disease from dementia with Lewy bodies and vascular cognitive impairment: a prospective study with pathological verification of diagnosis.
        Brain. 2009; 132: 195-203
        • Whitwell J.L.
        • Josephs K.A.
        • Murray M.E.
        • et al.
        MRI correlates of neurofibrillary tangle pathology at autopsy: a voxel-based morphometry study.
        Neurology. 2008; 71: 743-749
        • Braak H.
        • Braak E.
        Neuropathological stageing of Alzheimer-related changes.
        Acta Neuropathol. 1991; 82: 239-259