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Striatal Aβ peptide deposition mirrors dementia and differentiates DLB and PDD from other Parkinsonian syndromes
Neurobiology of Disease 41 (2011) 377–384
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Neurobiology of Disease j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y n b d i
Striatal Aβ peptide deposition mirrors dementia and differentiates DLB and PDD from other Parkinsonian syndromes M.E. Kalaitzakis ⁎, A.J. Walls, R.K.B. Pearce, S.M. Gentleman Neuropathology Unit, Centre for Neuroscience, Division of Experimental Medicine, Department of Medicine, Imperial College London, Charing Cross Campus, St Dunstan's Road, London, UK, W6 8RP
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Article history: Received 24 March 2010 Revised 29 September 2010 Accepted 7 October 2010 Available online 14 October 2010 Keywords: Parkinson's disease Dementia Striatum Amyloid-β peptide [11C]PIB ligand Dementia with Lewy bodies Neuropathology Lewy body disease
a b s t r a c t Recent neuropathological studies have described widespread amyloid-β peptide (Aβ) deposition in the striatum of patients with Lewy body disorders, particularly in Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB). However, positron emission tomography (PET) studies using the [11C]PIB ligand, binding to Aβ deposits, detects significant striatal pathology only in DLB and not in PDD. Employing immunohistochemistry, we examined striatal Aβ deposition in the caudate nucleus and putamen of 52 PD, 41 PDD, 14 DLB, 7 multiple system atrophy (MSA) and 14 progressive supranuclear palsy (PSP) cases in relation to the presence of dementia. PD, MSA and PSP cases showed little or no Aβ pathology in the striatum. In contrast, both PDD and DLB cases demonstrated significantly greater Aβ deposition in the striatum when compared to PD, MSA and PSP groups. We conclude that striatal Aβ pathology is common in both PDD and DLB and may reflect the development of dementia in these conditions. More detailed examination of the morphology of the Aβ pathology suggests that it is the presence of cored amyloid plaques in DLB, but not PDD, that underlies the differences seen in PET imaging. © 2010 Elsevier Inc. All rights reserved.
Introduction Parkinson's disease (PD) is a neurodegenerative disorder characterized by the gradual onset and progression of both motor and nonmotor disturbances (Fearnley and Lees, 1991). The defining pathological features of the disease are the loss of dopaminergic projection neurones of the substantia nigra pars compacta and locus coeruleus, as well as the presence of α-synuclein (αSyn) positive inclusions in cell bodies and cell processes of brainstem neurones, called Lewy bodies (LB) and Lewy neurites (LN), respectively. However, the pathology in PD exceeds the classical boundaries of the substantia nigra and locus coeruleus with involvement of multiple extranigral sites in both the central and peripheral (autonomic) nervous system (Braak and Braak, 2000). Co-morbid pathology characteristic of Alzheimer's disease (AD) is also often seen in patients with PD (Jellinger, 2009; Jellinger et al., 2002). Although PD is traditionally viewed as a movement disorder, nonmotor complications, including dementia, are commonly seen in PD patients, with a prevalence of up to 50% (Emre, 2003; Emre et al., 2007). The risk for dementia in PD (PDD) increases with age and duration of disease (Emre, 2003) with other risk factors including age at onset, an akinetic-rigid syndrome, depression, early autonomic ⁎ Corresponding author. E-mail address: [email protected] (M.E. Kalaitzakis). Available online on ScienceDirect (www.sciencedirect.com). 0969-9961/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2010.10.005
failure and a poor response to dopaminergic treatment (Aarsland et al., 1996; Emre et al., 2007; Hietanen and Teravainen, 1988; Reid et al., 1996). Despite a high incidence of dementia in PD (PDD) the precise anatomico-pathological basis for this remains unclear. Cortical, subcortical and limbic αSyn pathology have been linked to dementia in PD (Aarsland et al., 2005; Hurtig et al., 2000; Mattila et al., 2000), although other authors have described advanced αSyn pathology without clinical dementia (Parkkinen et al., 2005). We, and other groups, have demonstrated the presence of amyloid-β peptide (Aβ) pathology in the striatum of PDD and dementia with Lewy bodies (DLB) patients (Duda et al., 2002; Jellinger and Attems, 2006; Kalaitzakis et al., 2008; Liang et al., 2006). A possible distinction between PD, PDD and DLB on the basis of differences in Aβ striatal pathology has also been suggested (Jellinger and Attems, 2006; Kalaitzakis et al., 2008). Imaging studies, however, using Pittsburgh compound B ([11C]PIB) positron emission tomography (PET), as a marker of brain amyloid deposition, have demonstrated an increased Aβ load in the striatum of DLB but not PDD patients (Edison et al., 2008). In this immunohistochemical study we set out to explore the significance of striatal pathology in Lewy body diseases by investigating the extent and nature of Aβ deposition in the striatum of PD (n = 52), PDD (n = 41), DLB (n = 14), multiple system atrophy (MSA) (n = 7) and progressive supranuclear palsy (PSP) (n = 14) cases in relation to the presence of dementia.
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Materials and methods Neuropathological assessment Neuropathological diagnosis was based on αSyn, tau and Aβ immunohistochemistry of superior frontal gyrus, hippocampus, and midbrain. Confounding pathology was assessed on haematoxylin and eosin stained slides from 18 brain tissue blocks. Tissue was collected and processed according to an established protocol (Vonsattel et al., 1995). Neuropathological diagnosis was performed using international neuropathological consensus criteria for the definite diagnosis of PD (http://www.ICDNS.org). AD pathology of isocortical and/or entorhinal types was also assessed using the generic grading system posted at http://www.ICDNS.org and staged according to the scheme of Braak and Braak using AT8 immunohistochemistry (Braak et al., 2006). Cases with a co-morbid clinico-pathological diagnosis of AD were excluded from further analysis. All human tissue work was carried out under the ethical approval held by the UK Parkinson's Disease Society Tissue bank at Imperial College (REC Ref: 07/MRE09/ 72). Clinical assessment and selection of cases In the present study 128 cases collected from the UK Parkinson Disease Tissue Bank with PD and related neurodegenerative diseases were examined. This included 52 cases with PD (mean age at death 75.5 years), 41 cases with PDD (mean age at death 78.4 years), 14 cases with DLB (mean age at death 75.8 years), 7 cases with MSA (mean age at death 69.2 years) and 14 cases with PSP (mean age at death 77.9 years) (Table 1). Clinical data of cases were compiled retrospectively from hospital records by a movement disorder neurologist (RKBP). Only subjects evaluated by a clinician within 2 years prior to death and with complete clinical histories were included in this study. The clinical diagnoses of PD, PDD and DLB were based on published criteria (Daniel and Lees, 1993; Hurtig et al., 2000; McKeith et al., 2005). PD was considered to be present if the patient had at least 2 of the 4 cardinal symptoms (rigidity, hypokinesia, resting tremor and postural instability) and exhibited a positive response to levodopa (Daniel and Lees, 1993). Patients with PD who developed late dementia (N2 years after motor symptoms) were classified as PD with dementia (PDD) (Hurtig et al., 2000). The diagnosis of DLB was made if dementia preceded extrapyramidal symptoms by 1 year or they developed together within a 12-month period (McKeith et al., 2005). The diagnosis of dementia satisfied DSM-IV and ICD-10 clinical criteria. Retrospective case–note analysis is a well accepted method of case ascertainment and has often been used in clinico-pathological studies involving both dementia and parkinsonism (Kalaitzakis et al., 2009; Litvan et al., 1998; Papapetropoulos et al., 2005).
by examining the extent of deposits with semi-quantitative grading ranging from (0) 1 to 3 corresponding to (absent) sparse, moderate and frequent (Fig. 2) as previously described (Kalaitzakis et al., 2008). Sections were graded by two investigators blinded to diagnosis (MEK and AJW). Cohen's kappa statistic revealed an inter-rater reliability of 0.85 for Aβ lesions. Statistical analysis Statistical analysis was performed using the SPSS program version 15.0 for Windows XP and GraphPad Prism 4. The differences in Aβ burden as well as age at disease onset, age at death and duration of disease between the different diagnostic groups were analyzed with the non-parametric Mann–Whitney U-test. The association between Aβ burden and age at death, onset and duration of disease among the different diagnostic groups was assessed using Spearman's two-tailed correlation analysis (non-parametric). Cohen's kappa statistic was used to test inter-rater reliability for the Aβ semi-quantitative assessment between the two investigators. Intra-rater reliability was also examined by measuring the striatum of ten randomly selected subjects on six occasions at least a week apart. On each occasion, all operator-dependent processes (i.e. region of interest semi-quantitative assessment) were performed blinded to previous values. High intra-rater (and inter-rater) reliability was observed. P values b0.05 were considered significant. Results Clinical data The clinical characteristics of the different diagnostic groups examined are shown in Table 1. Statistical analysis demonstrated a significant difference with respect to age at disease onset between PD and DLB cases with the latter showing a later disease onset (61.7 vs. 69.5 years, respectively; p = 0.01). Cases with a diagnosis of MSA demonstrated a significantly earlier age at death than cases with a diagnosis of PDD (69.2 vs. 78.4 years, respectively; p = 0.04). Compared to PD and PDD cases the duration of disease was significantly shorter in DLB (p = 0.001, p = 0.003, respectively), MSA (p = 0.008, p = 0.004, respectively) and PSP (p = 0.01, p = 0.005, respectively) cases (Table 1). Tyrosine hydroxylase immunohistochemistry Tyrosine hydroxylase (TH) immunohistochemistry was performed in all cases and global patterns of staining in the CN and Put were assessed. All cases showed severe dopaminergic terminal denervation as indicated by with scant or essentially absent TH positivity (Fig. 1).
Immunohistochemistry
Striatal Aβ pathology
Immunohistochemistry was performed using standard protocols (Parkkinen et al., 2005). The primary antibody used in this study was 4G8 for visualization of Aβ plaques (Signet at a dilution of 1:2000) as recommended by a recent study from the BrainNet Europe Consortium (Alafuzoff et al., 2008) and tyrosine hydroxylase for examination of nigrostriatal fibers (Vector, Peterborough, UK, at a dilution of 1:30).
Aβ pathology was detected in all diagnostic groups to a varying extent. Aβ deposition was observed in the caudate nucleus and putamen, but no Aβ pathology was detected in the internal capsule. The caudato-lenticular gray bridges were also involved. The extent of Aβ burden in the different diagnostic groups is shown in Fig. 2. The morphology of Aβ deposits was similar to that we have described previously (Kalaitzakis et al., 2008) (Figs. 2 and 3). The most common form of Aβ striatal pathology was that of small, intensely stained ‘diffuse’ deposits that outnumbered large plaques by a factor of 3:1. Intensely stained diminutive (the size of a glial cell nucleus) and ‘dot-like’ aggregates were also present. Perhaps most significantly, all but one of the DLB cases demonstrated cored plaques (Fig. 3), with an average number of 20 cored plaques per section. By contrast none of the PDD, PD, MSA and PSP cases exhibited any cored plaques
Semi-quantitative assessment of Aβ pathology For each case, a representative section from the caudate nucleus (CN) and putamen (Put) was assessed for Aβ immunoreactivity. Sections were screened in their entirety at 10× primary magnification for overall deposit burden. Assessment of pathology was carried out
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Table 1 Clinical and neuropathological data of the diagnostic groups. Abbreviations: PD: non-demented Parkinson's disease, PDD: Parkinson's disease with dementia, DLB: Dementia with Lewy bodies, MSA: multiple system atrophy, MSA-P: Multiple System Atrophy parkinsonian subtype, MSA-C: Multiple System Atrophy cerebellar dysfunction subtype, PSP: progressive supranuclear palsy, yrs: years, m: male, f: female, na: not available. Age at onset (yrs)
Age at death (yrs)
Duration
Sex
Clinical diagnosis
Neuropath diagnosis
ICDNS AD GRADE (http://www.ICDNS.org)
Braak AD-stages
PD cases 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 Mean
74 62 68 62 54 41 49 65 75 60 69 86 59 67 69 60 67 68 64 58 35 69 52 66 51 67 73 53 57 42 76 64 64 78 73 78 49 67 61 37 69 47 67 62 66 58 54 46 66 44 69 72 61.7
77 72 78 72 72 75 76 75 82 74 76 89 74 77 82 79 75 82 75 76 54 83 58 81 73 80 82 82 75 62 85 79 73 86 78 87 50 81 75 74 79 72 75 76 72 60 79 77 70 78 79 76 75.5
3 10 10 10 18 34 27 10 7 14 7 3 15 10 13 19 8 14 11 18 19 14 6 15 22 13 9 29 18 20 9 15 9 8 5 9 1 14 14 37 10 25 8 14 6 2 25 31 4 34 10 4 14
m m m m f m m f m m m m f m f f m f m f m m f m m f m m m m m m m m m f m f m m f m m f m m m f m m m m
PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD
PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD
Isocortical Isocortical na Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical
I–entorhinal I I–entorhinal 0 I–entorhinal II 0–entorhinal II 0–entorhinal 0 I–entorhinal II 0–entorhinal I 0–entorhinal I 0–entorhinal I 0–entorhinal I 0–entorhinal I I–entorhinal III 0–entorhinal I I–entorhinal I 0–entorhinal 0 III–entothinal III III–entothinal III 0–entorhinal I 0–entorhinal I 0–entorhinal I 0–entorhinal 0 0–entorhinal I 0–entorhinal I 0–entorhinal I II–entorhinal III 0–entorhinal I 0–entorhinal 0 II–entorhinal 0 I–entorhinal II I–entorhinal II 0–entorhinal I 0–entorhinal I 0–entorhinal I I–entorhinal I I–entorhinal II 0–entorhinal II I–entorhinal 0 0–entorhinal I 0–entorhinal I I–entorhinal II I–entorhinal II 0–entorhinal I I–entorhinal II I–entorhinal I 0–entorhinal I III–entothinal III 0–entorhinal II 0–entorhinal I II–entorhinal II
I–II I–II na I–II I–II I–II I–II 0 I–II I–II I–II I–II I–II I–II I–II I–II I–II 0 I–II I–II 0 I–II I–II I–II I–II I–II I–II I–II I–II 0 I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II
PDD cases 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
75 57 67 62 54 56 67 57 77 72 69 64 57 73 85 67
84 80 81 71 78 70 85 75 82 81 75 82 73 84 87 77
9 23 14 9 24 14 18 18 5 9 6 18 16 11 2 10
m f f m m m f m m m m m m f m m
PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD
PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD
Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical
0–entorhinal I II–entorhinal III I–entorhinal I III–entorhinal III 0–entorhinal I IV–entorhinal III II–entorhinal I I–entorhinal II I–entorhinal II 0–entorhinal I IV–entorhinal III I–entorhinal II I–entorhinal II IV–entorhinal III 0–entorhinal I I–entorhinal I
0 I–II I–II I–II I–II III I–II I–II 0 I–II III–IV I–II I–II III–IV I–II I–II
I–entorhinal I I–entorhinal I
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Table 1 (continued) Age at onset (yrs)
Age at death (yrs)
Duration
Sex
Clinical diagnosis
Neuropath diagnosis
ICDNS AD GRADE (http://www.ICDNS.org)
Braak AD-stages
PDD cases 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 Mean
74 61 48 74 74 71 43 59 67 76 70 77 72 66 59 46 59 48 71 74 68 73 67 59 72 65.5
87 80 71 78 83 82 58 78 81 83 83 88 83 91 79 72 75 55 82 84 75 78 73 71 80 78.4
13 19 23 4 9 11 15 19 14 7 13 11 11 25 20 26 16 7 11 10 7 5 6 12 8 13
m m f m m m m f f f m f m m m m m m m f m m m m m
PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD
PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD
Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical
I–entorhinal II 0–entorhina III I–entorhinal II IV–entorhinal III 0–entorhinal I I–entorhinal II I–entorhinal II 0–entorhinal I I–entorhinal III IV–entorhinal III I–entorhinal II I–entorhinal II I–entorhinal II I–entorhinal 0 IV–entorhinal III I–entorhinal II 0–entorhinal I IV–entorhinal III I–entorhinal II 0–entorhinal I I–entorhinal II I–entorhinal I 0–entorhinal I 0–entorhinal II 0–entorhinal II
I–II III 0 III–IV I–II I–II I–II I–II I–II III I–II I–II I–II I–II III–IV I–II I–II III–IV I–II I–II I–II I–II I–II I–II I–II
DLB cases 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Mean
65 78 47 77 69 63 77 61 78 79 64 69 71 76 69.5
68 84 61 80 70 75 81 69 83 83 74 77 77 80 75.8
3 6 14 3 1 12 4 8 5 4 10 8 6 4 6.2
m m m m m m m m f f m m m m
DLB DLB DLB DLB DLB DLB DLB DLB DLB DLB DLB DLB DLB DLB
DLB DLB DLB DLB DLB DLB DLB DLB DLB DLB DLB DLB DLB DLB
Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical
IV–entorhinal III II–entorhinal II I–entorhinal II IV–entorhinal III II–entorhinal II IV–entorhinal III I–entorhinal III IV–entorhinal III I–entorhinal III IV–entorhinal III I–entorhinal III I–entorhinal II I–entorhinal II I–entorhinal III
III–IV I–II I–II III–IV I–II III–IV I–II III–IV I–II III–IV I–II I–II I–II I–II
MSA 1 2 3 4 5 6 7 Mean
32 78 66 74 66 68 57 63
42 86 71 78 69 76 63 69.2
10 8 5 4 3 8 6 6.2
m m m m m f f
MSA PSP MSA MSA MSA-C type PD PD
MSA MSA MSA-P type MSA MSA-C type MSA-C type MSA
Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical
0–entorhinal 0 I–entorhinal I 0–entorhinal I I–entorhinal I 0–entorhinal 0 0–entorhinal I I–entorhinal I
0 I–II I–II I–II 0 I–II I–II
PSP 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Mean
67 74 70 NA 56 74 60 79 65 65 66 68 80 78 69.3
82 78 77 88 66 79 69 82 74 69 75 74 88 90 77.9
15 4 7 NA 10 5 9 3 9 4 9 6 8 12 7.7
m m m m m f f f m m m m m m
Atypical PD PSP PSP PSP PSP Atypical PD PSP PSP PSP PSP PSP Atypical PD PD PD
PSP PSP PSP PSP PSP PSP PSP-P PSP PSP PSP PSP PSP PSP PSP
Isocortical na Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical
II–entorhinal III
I–II na I–II I–II I–II I–II I–II III–IV I–II I–II I–II I–II I–II I–II
in the striatum (Fig. 3). A blinded post hoc attribution of diagnosis on the basis of the presence or absence of cored plaques in the striatum, as the sole criterion, was also performed demonstrating a 95% accuracy in
I–entorhinal I III–entothinal III 0–entorhinal I I–entorhinal I I–entorhinal I IV–entorhinal III I–entorhinal I 0–entorhinal I 0–entorhinal I I–entorhinal I I–entorhinal II I–entorhinal II
differentiating DLB from non-DLB cases (i.e. PD, PDD, MSA and PSP). There was also a strong positive correlation between Aβ deposition in the caudate nucleus and putamen across all cases analyzed (ρ=0.0001).
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Fig. 1. Tyrosine hydroxylase (TH) immunohistochemistry in the striatum of PD, PDD, DLB, PSP and MSA cases. All cases studied demonstrated severe dopaminergic terminal denervation. Scant TH positivity in the striatum of a representative PD (A), PDD (B), DLB (C), PSP (D) and MSA (E) cases. Magnification: ×20. Abbreviations: PD: non-demented Parkinson's disease, PDD: Parkinson's disease with dementia, DLB: Dementia with Lewy bodies, MSA: multiple system atrophy, PSP: progressive supranuclear palsy.
Striatal pathology in PD, PDD and DLB In PD cases, Aβ deposition was absent in 36 out of the 52 cases (69%). The remaining PD cases showed minimal (i.e. a grading score of 1) Aβ pathology in both the caudate nucleus and putamen with only 7 cases exhibiting moderate to severe Aβ deposition. In contrast, Aβ deposition was present in 33/41 PDD cases (80%) and 27/41 (66%) demonstrated severe Aβ pathology. Aβ deposition among DLB cases was present in 12 out of 14 cases (86%). Ten out of the 12 positive DLB cases displayed a severe Aβ burden (83%). Aβ pathology was therefore significantly more frequent and of greater severity in PDD and DLB cases compared to the non-demented PD group (Fig. 2). Statistical analysis comparing the PD, PDD and DLB cases revealed a greater Aβ burden in PDD and DLB cases in both the caudate nucleus and putamen [PD vs. PDD (CN: p b 0.0001, Put: p b 0.0001) and PD vs. DLB (CN: p = 0.0002, put: p = 0.0004)] (Fig. 2). However, no significant difference in the extent of Aβ deposition was observed between PDD and DLB cases (CN: p = 0.3710, Put: p = 0.4777; Fig. 2). Striatal pathology in MSA and PSP and comparison to PD, PDD and DLB cases Striatal Aβ pathology was absent to minimal (i.e. a grading score of 0 to 1) in the majority of MSA and PSP cases. Only 3 PSP (21%) cases and 1 MSA (14%) case demonstrated moderate to severe striatal Aβ deposition. Interestingly these cases with increased striatal Aβ burden had cognitive impairment with the exception of 1 PSP case. Statistical analysis comparing PD, MSA and PSP cases demonstrated no statistical significant differences whereas both PDD and DLB cases exhibited a statistically significant increase in Aβ burden in the striatum when compared to the MSA and PSP cases (p values given in Fig. 2). Discussion Despite a high incidence of dementia in PD its specific anatomicopathological correlates remain largely undefined. Most clinicopathological studies point to cortical and limbic Lewy body pathology as a putative cause of dementia in PD (Aarsland et al., 2005; Apaydin et al., 2002; Ballard et al., 2004; Bertrand et al., 2004; Hurtig et al., 2000; Kalaitzakis et al., 2009). A strong association between LB pathology in the frontal cortex with dementia in PD has been reported (Mattila et al., 2000) while others have found a positive correlation between dementia and LB densities in the entorhinal cortex and anterior cingulate gyrus (Kovari et al., 2003). Although most clinicopathological studies of dementia in PD are retrospective, a prospective community-based study, using univariate regression analysis, has indicated that LB scores in cortical and limbic areas significantly associate with annual decline in Mini-Mental State Examination (MMSE) scores (Aarsland et al., 2005). Contesting these studies, others have found that a severe LB burden does not predict dementia in PD. Colosimo et al., demonstrated classic DLB pathology in PD patients without dementia (Colosimo et al., 2003) and Parkkinen
et al., have also questioned the significance of LB pathology in cortical and limbic structures for the development of dementia in PD (Parkkinen et al., 2005) with about 50% of cases with advanced pathology reaching Braak stages 5–6 not showing clinical signs of dementia. While LB pathology is a majorly proposed substrate of dementia in PD, AD pathology is also commonly found in the PDD brain and clinico-pathological studies have pointed to AD-type pathology as an important determinant of dementia in PD (Hughes et al., 1993; Jellinger, 1997; Jellinger et al., 2002). Although these studies describe cortical AD pathology, mostly plaques, as a putative substrate of dementia in PD, the significance of cortical plaques in both AD and PD has been debated (Arriagada et al., 1992; Mastaglia et al., 2003; Terry, 1996) as there have been inconsistent reports linking cortical Aβ burden and various measures of clinical deficit in both diseases (Vickers et al., 2000). Interestingly, more recent work has pointed to increased subcortical Aβ pathology in the striatum of DLB and PDD cases than non-demented PD cases (Jellinger and Attems, 2006; Liang et al., 2006). The results of the present study add support to previous reports and demonstrate that Aβ striatal pathology is a frequent pathological finding in Lewy body diseases. The high incidence and severity of Aβ pathology in the striatum of PDD and DLB cases as compared to the non-demented PD group indicates a strong association between Aβ deposition in the striatum and dementia in these conditions is in agreement with previous findings (Jellinger and Attems, 2006; Kalaitzakis et al., 2008). While the striatum is classically viewed as part of the motor loop, it also plays a major role in cognition and behavior with studies showing that lesions in the caudate nucleus can lead to the apathy and decreased recent memory (Schultz et al., 1997) characteristic of ‘subcortical dementia’. The finding of an association between striatal Aβ deposition and cognitive impairment (in PDD and DLB and also a small number of PSP and MSA cases) raises the question of the exact mechanism(s) by which pathology in the striatum might contribute to cognitive impairment. The striatum is a heterogeneous structure, which can be divided into striosome and matrix compartments, on the basis of the differential expression of a range of neurochemicals; including neurotransmitters and second messenger molecules (Holt et al., 1997; Prensa et al., 1999). Striosomes have been shown to connect with cortical and limbic structures, whilst the matrix is linked to sensorimotor and associative forebrain circuits (Saka et al., 2002). If Aβ deposition in the striatum occurs in certain areas of the striosome or matrix, then interference in limbic and associative circuits could be responsible for some of the cognitive changes seen in PDD and DLB. Further research is warranted to ascertain whether striatal pathology is associated with these specific striatal regions. Two recent studies have demonstrated an abundant Aβ burden in the striatum of DLB cases that was more pronounced than in PDD, pointing to a quantitative morphological distinction between these two disease states (Jellinger and Attems, 2006; Liang et al., 2006). In our study, however, no statistically significant difference in Aβ burden was found between PDD and DLB. However, we did find that the
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Fig. 2. Semi-quantitative ratings of pathology and severity of striatal Aβ pathology. Assessment of Aβ pathology in the striatum was carried out by examining the extent of plaques ranging from (0) 1 to 3 (A, B, C; ×10 stage objective) corresponding to (absent), sparse, moderate and frequent. Severity of Aβ pathology in the striatum of PD, PDD, DLB, MSA and PSP patients in the caudate nucleus (D) and putamen (E). The columns represent mean values ± SEM. ** denotes b 0.01 significance and * denotes b0.05 significance. Abbreviations: CN: caudate nucleus, Put: Putamen, PD: non-demented Parkinson's disease, PDD: Parkinson's disease with dementia, DLB: Dementia with Lewy bodies, MSA: multiple system atrophy, PSP: progressive supranuclear palsy. PD n = 52, PDD n = 41, DLB n = 14, MSA n = 7 and PSP n = 14.
striatal pathology of DLB cases was characterised by the presence of cored plaques, which were absent in the PDD, PD, MSA and PSP cases. This may go some way to explaining the apparent disparity with in vivo [11C]PIB/PET imaging studies which have found statistically significant differences between amyloid load in both PDD and DLB cases with minimal cortical or striatal PIB retention in most PDD patients, whereas DLB patients show high levels of both cortical and striatal PIB retention, similar to those found in AD (Edison et al., 2008; Gomperts et al., 2008; Maetzler et al., 2008). The PIB has a lower affinity for diffuse Aβ deposits, such as those we describe in the striatum of PDD cases, as opposed to the more densely aggregated form of Aβ found in cortical plaques of AD and DLB patients. We have examined a large number of cases (n = 128), using immunohistochemistry and have evaluated detailed clinical information. Although clinical details were available for all cases our report has
limitations germane to all retrospective clinico-pathological studies. Incomplete and inaccurate observations may have introduced a negative ascertainment bias into the detection of dementia. However, while acknowledging these limitations, we believe that the results of the present study indicate that there is a significant association between dementia and Aβ deposition in the striatum of PDD and DLB cases. Furthermore, examination of the morphology of the Aβ pathology suggests that it is the presence of cored amyloid plaques in DLB, but not PDD, that underlies the differences seen in PET imaging. Thus, anti-Aβ strategies targeting the striatum may be relevant in treating or preventing dementia in Lewy body disorders as well as in AD. Conflict of interest of authors None.
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Fig. 3. Photomicrographs of Aβ pathology in the striatum of DLB and PDD cases. Low power images (×10 stage objective) of DLB (A) and PDD (B) cases illustrating the similarities in the overall striatal Aβ burden in these two conditions. Cored plaques, found only in the DLB cases, are highlighted by asterisks in A. Higher power images (×20 stage objective) of cored plaques from three different DLB cases (C–E). These distinctive plaques have a very dense core and a diffuse halo of Aβ peptide. Diffuse plaques, with no specific focus of aggregation, were observed in both DLB and PDD cases (F–H). Abbreviations: PDD: Parkinson's disease with dementia, DLB: Dementia with Lewy bodies.
Acknowledgments This work was funded through a grant from the UK Parkinson's Disease Society (G-0709). Tissue samples were supplied by the Parkinson's Disease Society Tissue Bank at Imperial College London, funded by the Parkinson's Disease Society of the United Kingdom, registered charity 948776. The authors would like to thank Ms. Pey Peixuan for technical assistance of the TH staining. We express our deepest appreciation to the donors and their families for donating human brain tissue for research. The contribution of SMG to this work was also part funded by NIH grant AG12411.
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Neurobiology of Disease j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y n b d i
Striatal Aβ peptide deposition mirrors dementia and differentiates DLB and PDD from other Parkinsonian syndromes M.E. Kalaitzakis ⁎, A.J. Walls, R.K.B. Pearce, S.M. Gentleman Neuropathology Unit, Centre for Neuroscience, Division of Experimental Medicine, Department of Medicine, Imperial College London, Charing Cross Campus, St Dunstan's Road, London, UK, W6 8RP
a r t i c l e
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Article history: Received 24 March 2010 Revised 29 September 2010 Accepted 7 October 2010 Available online 14 October 2010 Keywords: Parkinson's disease Dementia Striatum Amyloid-β peptide [11C]PIB ligand Dementia with Lewy bodies Neuropathology Lewy body disease
a b s t r a c t Recent neuropathological studies have described widespread amyloid-β peptide (Aβ) deposition in the striatum of patients with Lewy body disorders, particularly in Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB). However, positron emission tomography (PET) studies using the [11C]PIB ligand, binding to Aβ deposits, detects significant striatal pathology only in DLB and not in PDD. Employing immunohistochemistry, we examined striatal Aβ deposition in the caudate nucleus and putamen of 52 PD, 41 PDD, 14 DLB, 7 multiple system atrophy (MSA) and 14 progressive supranuclear palsy (PSP) cases in relation to the presence of dementia. PD, MSA and PSP cases showed little or no Aβ pathology in the striatum. In contrast, both PDD and DLB cases demonstrated significantly greater Aβ deposition in the striatum when compared to PD, MSA and PSP groups. We conclude that striatal Aβ pathology is common in both PDD and DLB and may reflect the development of dementia in these conditions. More detailed examination of the morphology of the Aβ pathology suggests that it is the presence of cored amyloid plaques in DLB, but not PDD, that underlies the differences seen in PET imaging. © 2010 Elsevier Inc. All rights reserved.
Introduction Parkinson's disease (PD) is a neurodegenerative disorder characterized by the gradual onset and progression of both motor and nonmotor disturbances (Fearnley and Lees, 1991). The defining pathological features of the disease are the loss of dopaminergic projection neurones of the substantia nigra pars compacta and locus coeruleus, as well as the presence of α-synuclein (αSyn) positive inclusions in cell bodies and cell processes of brainstem neurones, called Lewy bodies (LB) and Lewy neurites (LN), respectively. However, the pathology in PD exceeds the classical boundaries of the substantia nigra and locus coeruleus with involvement of multiple extranigral sites in both the central and peripheral (autonomic) nervous system (Braak and Braak, 2000). Co-morbid pathology characteristic of Alzheimer's disease (AD) is also often seen in patients with PD (Jellinger, 2009; Jellinger et al., 2002). Although PD is traditionally viewed as a movement disorder, nonmotor complications, including dementia, are commonly seen in PD patients, with a prevalence of up to 50% (Emre, 2003; Emre et al., 2007). The risk for dementia in PD (PDD) increases with age and duration of disease (Emre, 2003) with other risk factors including age at onset, an akinetic-rigid syndrome, depression, early autonomic ⁎ Corresponding author. E-mail address: [email protected] (M.E. Kalaitzakis). Available online on ScienceDirect (www.sciencedirect.com). 0969-9961/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2010.10.005
failure and a poor response to dopaminergic treatment (Aarsland et al., 1996; Emre et al., 2007; Hietanen and Teravainen, 1988; Reid et al., 1996). Despite a high incidence of dementia in PD (PDD) the precise anatomico-pathological basis for this remains unclear. Cortical, subcortical and limbic αSyn pathology have been linked to dementia in PD (Aarsland et al., 2005; Hurtig et al., 2000; Mattila et al., 2000), although other authors have described advanced αSyn pathology without clinical dementia (Parkkinen et al., 2005). We, and other groups, have demonstrated the presence of amyloid-β peptide (Aβ) pathology in the striatum of PDD and dementia with Lewy bodies (DLB) patients (Duda et al., 2002; Jellinger and Attems, 2006; Kalaitzakis et al., 2008; Liang et al., 2006). A possible distinction between PD, PDD and DLB on the basis of differences in Aβ striatal pathology has also been suggested (Jellinger and Attems, 2006; Kalaitzakis et al., 2008). Imaging studies, however, using Pittsburgh compound B ([11C]PIB) positron emission tomography (PET), as a marker of brain amyloid deposition, have demonstrated an increased Aβ load in the striatum of DLB but not PDD patients (Edison et al., 2008). In this immunohistochemical study we set out to explore the significance of striatal pathology in Lewy body diseases by investigating the extent and nature of Aβ deposition in the striatum of PD (n = 52), PDD (n = 41), DLB (n = 14), multiple system atrophy (MSA) (n = 7) and progressive supranuclear palsy (PSP) (n = 14) cases in relation to the presence of dementia.
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Materials and methods Neuropathological assessment Neuropathological diagnosis was based on αSyn, tau and Aβ immunohistochemistry of superior frontal gyrus, hippocampus, and midbrain. Confounding pathology was assessed on haematoxylin and eosin stained slides from 18 brain tissue blocks. Tissue was collected and processed according to an established protocol (Vonsattel et al., 1995). Neuropathological diagnosis was performed using international neuropathological consensus criteria for the definite diagnosis of PD (http://www.ICDNS.org). AD pathology of isocortical and/or entorhinal types was also assessed using the generic grading system posted at http://www.ICDNS.org and staged according to the scheme of Braak and Braak using AT8 immunohistochemistry (Braak et al., 2006). Cases with a co-morbid clinico-pathological diagnosis of AD were excluded from further analysis. All human tissue work was carried out under the ethical approval held by the UK Parkinson's Disease Society Tissue bank at Imperial College (REC Ref: 07/MRE09/ 72). Clinical assessment and selection of cases In the present study 128 cases collected from the UK Parkinson Disease Tissue Bank with PD and related neurodegenerative diseases were examined. This included 52 cases with PD (mean age at death 75.5 years), 41 cases with PDD (mean age at death 78.4 years), 14 cases with DLB (mean age at death 75.8 years), 7 cases with MSA (mean age at death 69.2 years) and 14 cases with PSP (mean age at death 77.9 years) (Table 1). Clinical data of cases were compiled retrospectively from hospital records by a movement disorder neurologist (RKBP). Only subjects evaluated by a clinician within 2 years prior to death and with complete clinical histories were included in this study. The clinical diagnoses of PD, PDD and DLB were based on published criteria (Daniel and Lees, 1993; Hurtig et al., 2000; McKeith et al., 2005). PD was considered to be present if the patient had at least 2 of the 4 cardinal symptoms (rigidity, hypokinesia, resting tremor and postural instability) and exhibited a positive response to levodopa (Daniel and Lees, 1993). Patients with PD who developed late dementia (N2 years after motor symptoms) were classified as PD with dementia (PDD) (Hurtig et al., 2000). The diagnosis of DLB was made if dementia preceded extrapyramidal symptoms by 1 year or they developed together within a 12-month period (McKeith et al., 2005). The diagnosis of dementia satisfied DSM-IV and ICD-10 clinical criteria. Retrospective case–note analysis is a well accepted method of case ascertainment and has often been used in clinico-pathological studies involving both dementia and parkinsonism (Kalaitzakis et al., 2009; Litvan et al., 1998; Papapetropoulos et al., 2005).
by examining the extent of deposits with semi-quantitative grading ranging from (0) 1 to 3 corresponding to (absent) sparse, moderate and frequent (Fig. 2) as previously described (Kalaitzakis et al., 2008). Sections were graded by two investigators blinded to diagnosis (MEK and AJW). Cohen's kappa statistic revealed an inter-rater reliability of 0.85 for Aβ lesions. Statistical analysis Statistical analysis was performed using the SPSS program version 15.0 for Windows XP and GraphPad Prism 4. The differences in Aβ burden as well as age at disease onset, age at death and duration of disease between the different diagnostic groups were analyzed with the non-parametric Mann–Whitney U-test. The association between Aβ burden and age at death, onset and duration of disease among the different diagnostic groups was assessed using Spearman's two-tailed correlation analysis (non-parametric). Cohen's kappa statistic was used to test inter-rater reliability for the Aβ semi-quantitative assessment between the two investigators. Intra-rater reliability was also examined by measuring the striatum of ten randomly selected subjects on six occasions at least a week apart. On each occasion, all operator-dependent processes (i.e. region of interest semi-quantitative assessment) were performed blinded to previous values. High intra-rater (and inter-rater) reliability was observed. P values b0.05 were considered significant. Results Clinical data The clinical characteristics of the different diagnostic groups examined are shown in Table 1. Statistical analysis demonstrated a significant difference with respect to age at disease onset between PD and DLB cases with the latter showing a later disease onset (61.7 vs. 69.5 years, respectively; p = 0.01). Cases with a diagnosis of MSA demonstrated a significantly earlier age at death than cases with a diagnosis of PDD (69.2 vs. 78.4 years, respectively; p = 0.04). Compared to PD and PDD cases the duration of disease was significantly shorter in DLB (p = 0.001, p = 0.003, respectively), MSA (p = 0.008, p = 0.004, respectively) and PSP (p = 0.01, p = 0.005, respectively) cases (Table 1). Tyrosine hydroxylase immunohistochemistry Tyrosine hydroxylase (TH) immunohistochemistry was performed in all cases and global patterns of staining in the CN and Put were assessed. All cases showed severe dopaminergic terminal denervation as indicated by with scant or essentially absent TH positivity (Fig. 1).
Immunohistochemistry
Striatal Aβ pathology
Immunohistochemistry was performed using standard protocols (Parkkinen et al., 2005). The primary antibody used in this study was 4G8 for visualization of Aβ plaques (Signet at a dilution of 1:2000) as recommended by a recent study from the BrainNet Europe Consortium (Alafuzoff et al., 2008) and tyrosine hydroxylase for examination of nigrostriatal fibers (Vector, Peterborough, UK, at a dilution of 1:30).
Aβ pathology was detected in all diagnostic groups to a varying extent. Aβ deposition was observed in the caudate nucleus and putamen, but no Aβ pathology was detected in the internal capsule. The caudato-lenticular gray bridges were also involved. The extent of Aβ burden in the different diagnostic groups is shown in Fig. 2. The morphology of Aβ deposits was similar to that we have described previously (Kalaitzakis et al., 2008) (Figs. 2 and 3). The most common form of Aβ striatal pathology was that of small, intensely stained ‘diffuse’ deposits that outnumbered large plaques by a factor of 3:1. Intensely stained diminutive (the size of a glial cell nucleus) and ‘dot-like’ aggregates were also present. Perhaps most significantly, all but one of the DLB cases demonstrated cored plaques (Fig. 3), with an average number of 20 cored plaques per section. By contrast none of the PDD, PD, MSA and PSP cases exhibited any cored plaques
Semi-quantitative assessment of Aβ pathology For each case, a representative section from the caudate nucleus (CN) and putamen (Put) was assessed for Aβ immunoreactivity. Sections were screened in their entirety at 10× primary magnification for overall deposit burden. Assessment of pathology was carried out
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Table 1 Clinical and neuropathological data of the diagnostic groups. Abbreviations: PD: non-demented Parkinson's disease, PDD: Parkinson's disease with dementia, DLB: Dementia with Lewy bodies, MSA: multiple system atrophy, MSA-P: Multiple System Atrophy parkinsonian subtype, MSA-C: Multiple System Atrophy cerebellar dysfunction subtype, PSP: progressive supranuclear palsy, yrs: years, m: male, f: female, na: not available. Age at onset (yrs)
Age at death (yrs)
Duration
Sex
Clinical diagnosis
Neuropath diagnosis
ICDNS AD GRADE (http://www.ICDNS.org)
Braak AD-stages
PD cases 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 Mean
74 62 68 62 54 41 49 65 75 60 69 86 59 67 69 60 67 68 64 58 35 69 52 66 51 67 73 53 57 42 76 64 64 78 73 78 49 67 61 37 69 47 67 62 66 58 54 46 66 44 69 72 61.7
77 72 78 72 72 75 76 75 82 74 76 89 74 77 82 79 75 82 75 76 54 83 58 81 73 80 82 82 75 62 85 79 73 86 78 87 50 81 75 74 79 72 75 76 72 60 79 77 70 78 79 76 75.5
3 10 10 10 18 34 27 10 7 14 7 3 15 10 13 19 8 14 11 18 19 14 6 15 22 13 9 29 18 20 9 15 9 8 5 9 1 14 14 37 10 25 8 14 6 2 25 31 4 34 10 4 14
m m m m f m m f m m m m f m f f m f m f m m f m m f m m m m m m m m m f m f m m f m m f m m m f m m m m
PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD
PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD
Isocortical Isocortical na Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical
I–entorhinal I I–entorhinal 0 I–entorhinal II 0–entorhinal II 0–entorhinal 0 I–entorhinal II 0–entorhinal I 0–entorhinal I 0–entorhinal I 0–entorhinal I 0–entorhinal I I–entorhinal III 0–entorhinal I I–entorhinal I 0–entorhinal 0 III–entothinal III III–entothinal III 0–entorhinal I 0–entorhinal I 0–entorhinal I 0–entorhinal 0 0–entorhinal I 0–entorhinal I 0–entorhinal I II–entorhinal III 0–entorhinal I 0–entorhinal 0 II–entorhinal 0 I–entorhinal II I–entorhinal II 0–entorhinal I 0–entorhinal I 0–entorhinal I I–entorhinal I I–entorhinal II 0–entorhinal II I–entorhinal 0 0–entorhinal I 0–entorhinal I I–entorhinal II I–entorhinal II 0–entorhinal I I–entorhinal II I–entorhinal I 0–entorhinal I III–entothinal III 0–entorhinal II 0–entorhinal I II–entorhinal II
I–II I–II na I–II I–II I–II I–II 0 I–II I–II I–II I–II I–II I–II I–II I–II I–II 0 I–II I–II 0 I–II I–II I–II I–II I–II I–II I–II I–II 0 I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II I–II
PDD cases 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
75 57 67 62 54 56 67 57 77 72 69 64 57 73 85 67
84 80 81 71 78 70 85 75 82 81 75 82 73 84 87 77
9 23 14 9 24 14 18 18 5 9 6 18 16 11 2 10
m f f m m m f m m m m m m f m m
PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD
PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD
Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical
0–entorhinal I II–entorhinal III I–entorhinal I III–entorhinal III 0–entorhinal I IV–entorhinal III II–entorhinal I I–entorhinal II I–entorhinal II 0–entorhinal I IV–entorhinal III I–entorhinal II I–entorhinal II IV–entorhinal III 0–entorhinal I I–entorhinal I
0 I–II I–II I–II I–II III I–II I–II 0 I–II III–IV I–II I–II III–IV I–II I–II
I–entorhinal I I–entorhinal I
(continued on next page)
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Table 1 (continued) Age at onset (yrs)
Age at death (yrs)
Duration
Sex
Clinical diagnosis
Neuropath diagnosis
ICDNS AD GRADE (http://www.ICDNS.org)
Braak AD-stages
PDD cases 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 Mean
74 61 48 74 74 71 43 59 67 76 70 77 72 66 59 46 59 48 71 74 68 73 67 59 72 65.5
87 80 71 78 83 82 58 78 81 83 83 88 83 91 79 72 75 55 82 84 75 78 73 71 80 78.4
13 19 23 4 9 11 15 19 14 7 13 11 11 25 20 26 16 7 11 10 7 5 6 12 8 13
m m f m m m m f f f m f m m m m m m m f m m m m m
PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD PDD
PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD PD
Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical
I–entorhinal II 0–entorhina III I–entorhinal II IV–entorhinal III 0–entorhinal I I–entorhinal II I–entorhinal II 0–entorhinal I I–entorhinal III IV–entorhinal III I–entorhinal II I–entorhinal II I–entorhinal II I–entorhinal 0 IV–entorhinal III I–entorhinal II 0–entorhinal I IV–entorhinal III I–entorhinal II 0–entorhinal I I–entorhinal II I–entorhinal I 0–entorhinal I 0–entorhinal II 0–entorhinal II
I–II III 0 III–IV I–II I–II I–II I–II I–II III I–II I–II I–II I–II III–IV I–II I–II III–IV I–II I–II I–II I–II I–II I–II I–II
DLB cases 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Mean
65 78 47 77 69 63 77 61 78 79 64 69 71 76 69.5
68 84 61 80 70 75 81 69 83 83 74 77 77 80 75.8
3 6 14 3 1 12 4 8 5 4 10 8 6 4 6.2
m m m m m m m m f f m m m m
DLB DLB DLB DLB DLB DLB DLB DLB DLB DLB DLB DLB DLB DLB
DLB DLB DLB DLB DLB DLB DLB DLB DLB DLB DLB DLB DLB DLB
Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical
IV–entorhinal III II–entorhinal II I–entorhinal II IV–entorhinal III II–entorhinal II IV–entorhinal III I–entorhinal III IV–entorhinal III I–entorhinal III IV–entorhinal III I–entorhinal III I–entorhinal II I–entorhinal II I–entorhinal III
III–IV I–II I–II III–IV I–II III–IV I–II III–IV I–II III–IV I–II I–II I–II I–II
MSA 1 2 3 4 5 6 7 Mean
32 78 66 74 66 68 57 63
42 86 71 78 69 76 63 69.2
10 8 5 4 3 8 6 6.2
m m m m m f f
MSA PSP MSA MSA MSA-C type PD PD
MSA MSA MSA-P type MSA MSA-C type MSA-C type MSA
Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical
0–entorhinal 0 I–entorhinal I 0–entorhinal I I–entorhinal I 0–entorhinal 0 0–entorhinal I I–entorhinal I
0 I–II I–II I–II 0 I–II I–II
PSP 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Mean
67 74 70 NA 56 74 60 79 65 65 66 68 80 78 69.3
82 78 77 88 66 79 69 82 74 69 75 74 88 90 77.9
15 4 7 NA 10 5 9 3 9 4 9 6 8 12 7.7
m m m m m f f f m m m m m m
Atypical PD PSP PSP PSP PSP Atypical PD PSP PSP PSP PSP PSP Atypical PD PD PD
PSP PSP PSP PSP PSP PSP PSP-P PSP PSP PSP PSP PSP PSP PSP
Isocortical na Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical Isocortical
II–entorhinal III
I–II na I–II I–II I–II I–II I–II III–IV I–II I–II I–II I–II I–II I–II
in the striatum (Fig. 3). A blinded post hoc attribution of diagnosis on the basis of the presence or absence of cored plaques in the striatum, as the sole criterion, was also performed demonstrating a 95% accuracy in
I–entorhinal I III–entothinal III 0–entorhinal I I–entorhinal I I–entorhinal I IV–entorhinal III I–entorhinal I 0–entorhinal I 0–entorhinal I I–entorhinal I I–entorhinal II I–entorhinal II
differentiating DLB from non-DLB cases (i.e. PD, PDD, MSA and PSP). There was also a strong positive correlation between Aβ deposition in the caudate nucleus and putamen across all cases analyzed (ρ=0.0001).
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Fig. 1. Tyrosine hydroxylase (TH) immunohistochemistry in the striatum of PD, PDD, DLB, PSP and MSA cases. All cases studied demonstrated severe dopaminergic terminal denervation. Scant TH positivity in the striatum of a representative PD (A), PDD (B), DLB (C), PSP (D) and MSA (E) cases. Magnification: ×20. Abbreviations: PD: non-demented Parkinson's disease, PDD: Parkinson's disease with dementia, DLB: Dementia with Lewy bodies, MSA: multiple system atrophy, PSP: progressive supranuclear palsy.
Striatal pathology in PD, PDD and DLB In PD cases, Aβ deposition was absent in 36 out of the 52 cases (69%). The remaining PD cases showed minimal (i.e. a grading score of 1) Aβ pathology in both the caudate nucleus and putamen with only 7 cases exhibiting moderate to severe Aβ deposition. In contrast, Aβ deposition was present in 33/41 PDD cases (80%) and 27/41 (66%) demonstrated severe Aβ pathology. Aβ deposition among DLB cases was present in 12 out of 14 cases (86%). Ten out of the 12 positive DLB cases displayed a severe Aβ burden (83%). Aβ pathology was therefore significantly more frequent and of greater severity in PDD and DLB cases compared to the non-demented PD group (Fig. 2). Statistical analysis comparing the PD, PDD and DLB cases revealed a greater Aβ burden in PDD and DLB cases in both the caudate nucleus and putamen [PD vs. PDD (CN: p b 0.0001, Put: p b 0.0001) and PD vs. DLB (CN: p = 0.0002, put: p = 0.0004)] (Fig. 2). However, no significant difference in the extent of Aβ deposition was observed between PDD and DLB cases (CN: p = 0.3710, Put: p = 0.4777; Fig. 2). Striatal pathology in MSA and PSP and comparison to PD, PDD and DLB cases Striatal Aβ pathology was absent to minimal (i.e. a grading score of 0 to 1) in the majority of MSA and PSP cases. Only 3 PSP (21%) cases and 1 MSA (14%) case demonstrated moderate to severe striatal Aβ deposition. Interestingly these cases with increased striatal Aβ burden had cognitive impairment with the exception of 1 PSP case. Statistical analysis comparing PD, MSA and PSP cases demonstrated no statistical significant differences whereas both PDD and DLB cases exhibited a statistically significant increase in Aβ burden in the striatum when compared to the MSA and PSP cases (p values given in Fig. 2). Discussion Despite a high incidence of dementia in PD its specific anatomicopathological correlates remain largely undefined. Most clinicopathological studies point to cortical and limbic Lewy body pathology as a putative cause of dementia in PD (Aarsland et al., 2005; Apaydin et al., 2002; Ballard et al., 2004; Bertrand et al., 2004; Hurtig et al., 2000; Kalaitzakis et al., 2009). A strong association between LB pathology in the frontal cortex with dementia in PD has been reported (Mattila et al., 2000) while others have found a positive correlation between dementia and LB densities in the entorhinal cortex and anterior cingulate gyrus (Kovari et al., 2003). Although most clinicopathological studies of dementia in PD are retrospective, a prospective community-based study, using univariate regression analysis, has indicated that LB scores in cortical and limbic areas significantly associate with annual decline in Mini-Mental State Examination (MMSE) scores (Aarsland et al., 2005). Contesting these studies, others have found that a severe LB burden does not predict dementia in PD. Colosimo et al., demonstrated classic DLB pathology in PD patients without dementia (Colosimo et al., 2003) and Parkkinen
et al., have also questioned the significance of LB pathology in cortical and limbic structures for the development of dementia in PD (Parkkinen et al., 2005) with about 50% of cases with advanced pathology reaching Braak stages 5–6 not showing clinical signs of dementia. While LB pathology is a majorly proposed substrate of dementia in PD, AD pathology is also commonly found in the PDD brain and clinico-pathological studies have pointed to AD-type pathology as an important determinant of dementia in PD (Hughes et al., 1993; Jellinger, 1997; Jellinger et al., 2002). Although these studies describe cortical AD pathology, mostly plaques, as a putative substrate of dementia in PD, the significance of cortical plaques in both AD and PD has been debated (Arriagada et al., 1992; Mastaglia et al., 2003; Terry, 1996) as there have been inconsistent reports linking cortical Aβ burden and various measures of clinical deficit in both diseases (Vickers et al., 2000). Interestingly, more recent work has pointed to increased subcortical Aβ pathology in the striatum of DLB and PDD cases than non-demented PD cases (Jellinger and Attems, 2006; Liang et al., 2006). The results of the present study add support to previous reports and demonstrate that Aβ striatal pathology is a frequent pathological finding in Lewy body diseases. The high incidence and severity of Aβ pathology in the striatum of PDD and DLB cases as compared to the non-demented PD group indicates a strong association between Aβ deposition in the striatum and dementia in these conditions is in agreement with previous findings (Jellinger and Attems, 2006; Kalaitzakis et al., 2008). While the striatum is classically viewed as part of the motor loop, it also plays a major role in cognition and behavior with studies showing that lesions in the caudate nucleus can lead to the apathy and decreased recent memory (Schultz et al., 1997) characteristic of ‘subcortical dementia’. The finding of an association between striatal Aβ deposition and cognitive impairment (in PDD and DLB and also a small number of PSP and MSA cases) raises the question of the exact mechanism(s) by which pathology in the striatum might contribute to cognitive impairment. The striatum is a heterogeneous structure, which can be divided into striosome and matrix compartments, on the basis of the differential expression of a range of neurochemicals; including neurotransmitters and second messenger molecules (Holt et al., 1997; Prensa et al., 1999). Striosomes have been shown to connect with cortical and limbic structures, whilst the matrix is linked to sensorimotor and associative forebrain circuits (Saka et al., 2002). If Aβ deposition in the striatum occurs in certain areas of the striosome or matrix, then interference in limbic and associative circuits could be responsible for some of the cognitive changes seen in PDD and DLB. Further research is warranted to ascertain whether striatal pathology is associated with these specific striatal regions. Two recent studies have demonstrated an abundant Aβ burden in the striatum of DLB cases that was more pronounced than in PDD, pointing to a quantitative morphological distinction between these two disease states (Jellinger and Attems, 2006; Liang et al., 2006). In our study, however, no statistically significant difference in Aβ burden was found between PDD and DLB. However, we did find that the
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Fig. 2. Semi-quantitative ratings of pathology and severity of striatal Aβ pathology. Assessment of Aβ pathology in the striatum was carried out by examining the extent of plaques ranging from (0) 1 to 3 (A, B, C; ×10 stage objective) corresponding to (absent), sparse, moderate and frequent. Severity of Aβ pathology in the striatum of PD, PDD, DLB, MSA and PSP patients in the caudate nucleus (D) and putamen (E). The columns represent mean values ± SEM. ** denotes b 0.01 significance and * denotes b0.05 significance. Abbreviations: CN: caudate nucleus, Put: Putamen, PD: non-demented Parkinson's disease, PDD: Parkinson's disease with dementia, DLB: Dementia with Lewy bodies, MSA: multiple system atrophy, PSP: progressive supranuclear palsy. PD n = 52, PDD n = 41, DLB n = 14, MSA n = 7 and PSP n = 14.
striatal pathology of DLB cases was characterised by the presence of cored plaques, which were absent in the PDD, PD, MSA and PSP cases. This may go some way to explaining the apparent disparity with in vivo [11C]PIB/PET imaging studies which have found statistically significant differences between amyloid load in both PDD and DLB cases with minimal cortical or striatal PIB retention in most PDD patients, whereas DLB patients show high levels of both cortical and striatal PIB retention, similar to those found in AD (Edison et al., 2008; Gomperts et al., 2008; Maetzler et al., 2008). The PIB has a lower affinity for diffuse Aβ deposits, such as those we describe in the striatum of PDD cases, as opposed to the more densely aggregated form of Aβ found in cortical plaques of AD and DLB patients. We have examined a large number of cases (n = 128), using immunohistochemistry and have evaluated detailed clinical information. Although clinical details were available for all cases our report has
limitations germane to all retrospective clinico-pathological studies. Incomplete and inaccurate observations may have introduced a negative ascertainment bias into the detection of dementia. However, while acknowledging these limitations, we believe that the results of the present study indicate that there is a significant association between dementia and Aβ deposition in the striatum of PDD and DLB cases. Furthermore, examination of the morphology of the Aβ pathology suggests that it is the presence of cored amyloid plaques in DLB, but not PDD, that underlies the differences seen in PET imaging. Thus, anti-Aβ strategies targeting the striatum may be relevant in treating or preventing dementia in Lewy body disorders as well as in AD. Conflict of interest of authors None.
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Fig. 3. Photomicrographs of Aβ pathology in the striatum of DLB and PDD cases. Low power images (×10 stage objective) of DLB (A) and PDD (B) cases illustrating the similarities in the overall striatal Aβ burden in these two conditions. Cored plaques, found only in the DLB cases, are highlighted by asterisks in A. Higher power images (×20 stage objective) of cored plaques from three different DLB cases (C–E). These distinctive plaques have a very dense core and a diffuse halo of Aβ peptide. Diffuse plaques, with no specific focus of aggregation, were observed in both DLB and PDD cases (F–H). Abbreviations: PDD: Parkinson's disease with dementia, DLB: Dementia with Lewy bodies.
Acknowledgments This work was funded through a grant from the UK Parkinson's Disease Society (G-0709). Tissue samples were supplied by the Parkinson's Disease Society Tissue Bank at Imperial College London, funded by the Parkinson's Disease Society of the United Kingdom, registered charity 948776. The authors would like to thank Ms. Pey Peixuan for technical assistance of the TH staining. We express our deepest appreciation to the donors and their families for donating human brain tissue for research. The contribution of SMG to this work was also part funded by NIH grant AG12411.
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