Cortical PIB binding in Lewy body disease is associated with Alzheimer-like characteristics

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Abstract

About one fourth of Lewy body disease (LBD) patients show cortical β-amyloid load, basically a hallmark of Alzheimer disease (AD). Using [11C]PIB-PET, we tested whether LBD patients with β-amyloid burden differ from those without with respect to demographic, clinical, biochemical and genetic parameters.

Thirty-five LBD subjects (9 patients with Lewy body dementia, DLB; 12 demented Parkinson patients, PDD; 14 non-demented PD, PDND) underwent [11C]PIB-PET, and were classified as either PIB(+) or PIB(−) according to cortical PIB uptake. PIB(+) and PIB(−) patients were then compared according to demographic, clinical, biochemical and genetic parameters.

None of the PDND, but four PDD and four DLB subjects were PIB(+). In PIB(+) subjects, ApoE4 prevalence was higher, CSF Abeta42 levels were lower and, among demented patients, PIB-binding was associated with a lower MMSE score. Motor symptoms were not associated with PIB binding. Thus, LBD patients with cortical β-amyloid show characteristics usually observed in AD.

Introduction

Due to abnormal neuronal α-synuclein inclusions (Lewy bodies, LB), dementia with Lewy bodies (DLB), Parkinson disease with dementia (PDD) and Parkinson disease without dementia (PDND) are subsumed under the term “Lewy body disease” (Lippa et al., 2007). According to post-mortem data, it can be estimated that about one fourth of Lewy body disease patients suffer also from cortical β-amyloid burden, with the highest proportion in DLB subjects, followed by PDD subjects (Boller et al., 1980, Braak et al., 2005, Hughes et al., 1993, Jellinger et al., 2003). Conversely, about 15–20% of demented patients with enough cortical β-amyloid plaques to meet neuropathological criteria for Alzheimer disease (AD) also have cortical and subcortical Lewy bodies (LB) previously thought to be pathognomonic for Parkinson disease (Hulette et al., 1995, Ranginwala et al., 2008). Clinically, most (Forstl et al., 1993, Hansen et al., 1990) but not all (Yokota et al., 2007) of these Lewy body disease patients with concomitant cortical β-amyloid pathology suffer from Parkinsonian symptoms, and may reveal greater deficits in attention, fluency, and visuospatial processing than Lewy body disease patients without this pathological feature (Hansen et al., 1990). Jellinger et al. (2003) reported that DLB cases with severe cortical β-amyloid pathology present with initial dementia, often with fluctuating cognition, while parkinsonism was not regularly observed. There is an ongoing debate as to whether these subjects with co-occurring LB and β-amyloid pathology comprise a variant of Lewy body disease (“AD variant of Lewy body disease”), or would be better placed within a larger category of AD disease (“Lewy body variant of AD”).

With the advance of new neuroimaging techniques there exists for the first time the possibility to investigate in vivo whether Lewy body disease patients with cortical β-amyloid burden display different demographic, clinical, genetic and biochemical characteristics in comparison to Lewy body disease patients without.

The 11C-labeled amyloid ligand Pittsburgh Compound B ([11C]PIB) is currently the best established ligand to assess in-vivo β-amyloid burden. Increased cortical PIB-uptake has been shown in AD patients and subjects at risk for the development of AD (Engler et al., 2006, Fagan et al., 2006, Kemppainen et al., 2007, Klunk et al., 2004, Mintun et al., 2006, Pike et al., 2007, Price et al., 2005, Rowe et al., 2007). This PIB uptake is in accordance with the previously described distribution and formation stages (i.e. the stages of deposition) of β-amyloid pathology in AD (Braak and Braak, 1997, Rowe et al., 2007, Thal et al., 2002). An increase in cortical PIB has also been demonstrated in DLB patients (Edison et al., 2008, Gomperts et al., 2008, Rowe et al., 2007), in PDD patients (Edison et al., 2008, Gomperts et al., 2008) and in healthy controls (Gomperts et al., 2008, Pike et al., 2007, Rowe et al., 2007). In-vitro studies strongly indicate that elevated cortical PIB binding is due to β-amyloid and not to (cortical) LB pathology (Fodero-Tavoletti et al., 2007, Ye et al., 2008).

The objective of this study was to identify group differences between Lewy body disease subjects with increased cortical PIB uptake (PIB(+)) and those without (PIB(−)) in vivo, with special emphasis on parameters obtainable in an outpatient clinical setting. We followed the hypothesis that in Lewy body disease, PIB(+) differ from PIB(−) subjects with respect to demographic, biochemical and genetic parameters as well as to motor and non-motor symptoms, possibly displaying characteristics usually found in AD.

Section snippets

Participants

Thirty-five patients with Lewy body disease (9 DLB, 12 PDD and 14 PDND) were selected by experienced neurologists (D.B, W.M.) from the ward and the outpatient clinic at the Neurodegenerative Department of the University of Tuebingen within 12 months (2006–2007). The local ethics committee approved the study, and informed consent was obtained from all participants. PDND and PDD subjects fulfilled the UKPDS Brain Bank criteria for diagnosis of Parkinson disease (Gibb and Lees, 1988), PDD subjects

PIB binding

None of the 14 PDND (highest SUVR: 1.25) but 4 of 9 DLB (lowest SUVR: 1.65), and 4 of 12 PDD (lowest: 1.51) were classified as PIB(+) with a similar SUVRCORTEX as the 6 AD subjects investigated previously (lowest 1.63) (Fig. 1).

All PIB(+) subjects showed a similar cortical PIB pattern with increased uptake particularly in the frontal cortex, in the posterior cingulate along with the adjacent cuneus/precuneus, in the temporoparietooccipital cortex and in the striatum (Fig. 2). This pattern was

Discussion

In accordance with three other recent PET-studies (Edison et al., 2008, Gomperts et al., 2008, Rowe et al., 2007), and in accordance with post-mortem results (Boller et al., 1980, Jellinger, 2006, Jellinger et al., 2003), we observed cortical PIB binding in a relevant portion of Lewy body disease patients, and we extend the literature by comparing PIB binding with demographic, clinical, genetic and biochemical parameters.

We found lower Abeta42 levels in PIB(+) patients, compared to PIB(−)

Acknowledgments

The authors wish to thank all patients, who took part in the study. The study was partly supported by the AKF program (Number 201-0-0) of the University of Tuebingen and the Robert Bosch Foundation (Number 32.5.1141.0019.0).

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