Table 1.
Summary of relevant neuropathological evidence of Alzheimer-type co-pathology in Parkinson’s disease ranging from few pre-α-synuclein era examples to more recent clinicopathological studies
| Reference | Year | Sample | Main outcomes | Main findings | Comments |
| Hakim &Mathieson [9] | 1979 | 34 PD | Dementia cases | 19 PDD cases (56%) | |
| Plaques &tangles | 33 PD cases with plaques &tangles | ||||
| Boller et al. [10] | 1980 | 36 PD cases (29 with adequate clinical data) | Dementia cases | 9 cases with severe dementia (31%) | |
| Plaques &tangles | 7 cases with mild dementia (24%) | ||||
| Plaques &tangles in 15/36 (42%): | |||||
| →9/9 (100%) with severe dementia | •Retrospective | ||||
| →3/7 (43%) with mild dementia | |||||
| →3/13 (23%) with no dementia | •Pre-α-synuclein era study (ubiquitin immune-staining) | ||||
| AD changes = 6-fold in PD (33&) relative to controls (5.1%) | |||||
| AD changes = shorter survival than no AD changes | |||||
| Jendroska et al. [11] | 1996 | 50 PD cases79 controls | Dementia casesPlaques &tanglesVascular damageHydrocephalus | 23 patients had dementia including all 9 cases with widespread cortical Aβ | •Definition of dementia? |
| 5 of 17 controls with widespread cortical Aβwere not demented | |||||
| 14 patients with dementia unrelated to Aβ | |||||
| → 5 = not explained by histological changes | |||||
| → 4 = vascular damage | |||||
| → 3 = numerous cortical Lewy bodies | |||||
| → 2 = hydrocephalus | |||||
| Mattila et al. [12] | 1998 | 44 PD cases | CERAD neuropathological assessment | At least 1 cortical Lewy body in 93% | |
| Reisberg’s global deterioration scale (GDS) Lewy &Alzheimer-changes in the substantia nigra, amygdala, hippocampus and cortex | 43% of cases with Alzheimer-changes | ||||
| Total cortical Lewy bodies+temporal neurofibrillary tangles associated with cognitive impairment | |||||
| Mattila et al. [14] | 2000 | 45 PD cases | Amygdala, hippocampus+6 cortical gyri | At least 1 cortical Lewy body in 95% | |
| Lewy body and Alzheimer type changes | 40% of cases with Alzheimer-changes | ||||
| Lewy bodies density correlated with plaques rather than tangles | •Retrospective | ||||
| Frontal Lewy bodies = significant predictor of cognitive impairment | •α-synuclein immunostaining | ||||
| Hurtig et al. [15] | 2000 | 20 PDND22 PDD | α-synuclein, ubiquitin and thioflavine S stainings | α-synuclein+cortical Lewy bodies → highly sensitive (91%) and specific (90%) neuropathologic markers of dementia in PD | |
| Slightly more sensitive than ubiquitin+cortical Lewy bodies | |||||
| Better indicators of dementia than angles, plaques, or dystrophic neurites. | |||||
| Apaydin et al. [16] | 2002 | 9 PDND12 PDD | Hematoxylin-eosin, Bielschowsky and thioflavin S stains+α-synuclein and tau immunostainings | 12 PDD → diffuse or transitional Lewy bodies | |
| Mean cortical &limbic Lewy body counts 10-fold greater in PDD > PDND | |||||
| Cortical Lewy body counts significantly correlated to plaques &tangles | |||||
| Colosimo et al. [17] | 2005 | 38 PD (21 = cognitive impairment) | α-synuclein and tau immunostainings | Of the 17 patients without cognitive impairment, 9 had transitional and 8 had neocortical Lewy bodies | |
| Kovari et al. [18] | 2003 | 22 PD | Clinical dementia rating scale (CDR)+quantification of Lewy bodies, tangles and plaques in areas 9, 21, 24, 40 and entorhinal cx | CDR correlated with entorhinal and area 24 Lewy scores | •Retrospective |
| Entorhinal Lewy &plaque densities explained 36.2% and 19.3% of CDR variability, respectively | •α-synuclein immunostaining | ||||
| Braak et al. [19] | 2005 | 88 PD | MMSE, Braak stages for α-synuclein and tau pathologies | MMSE scores correlated with α-synuclein neuropathologic stages | |
| Higher neurofibrillary pathology stages and Aβ deposition in cognitively impaired cases | |||||
| Pletnikova et al. [20] | 2005 | 21 PD+DLB | α-synuclein and Aβ immunohistochemistry and immunoblots | Few or no cortical Lewy bodies in brains without Aβ | |
| The opposite in brains with Aβ (specifically in the cingulate cortex) | |||||
| Aarsland et al. [21] | 2005 | 22 PD | Aβ CERAD classification and Braak stages for α-synuclein and tau | 18 developed PDD → none met AD neuropathological definition | |
| Cortical Lewy bodies were the main substrate of cognitive impairment | •Prospective | ||||
| Ballard et al. [22] | 2006 | 28 PDD+29 DLB | MMSE &UPDRS | Longer time from parkinsonism to dementia was associated with less severe cortical α-synuclein pathology and CERAD Aβ scores, but not Braak staging | •α-synuclein immunostaining |
| Haliday et al. [23] | 2008 | 29 PDND+52 PDD+6 DLB | Cases with shorter survivals had more Lewy and plaque pathology | ||
| Sabbagh et al. [24] | 2009 | 28 PDD+AD23 PDD-AD | PDD+AD subjects were older at onset and death, and progressed faster to dementia; about one half of cases met AD neuropathological criteria | ||
| Jellinger &Attems [25] | 2008 | 54 PDND+44 PDD+20 DLB | α-synuclein, tau &Aβ immunohistochemistry | Braak stages for α-synuclein &tau as well as cortical Aß plaque load, and generalized cerebral amyloid angiopathy or CAA) were significantly higher/more severe in DLB and PDD than in PD | |
| Lashley et al. [26] | 2008 | 40 PD | Semiquantitative Aβ plaques &CAA scores | Aβ load correlated with cortical Lewy burden | |
| 20 controls | Morphometric approach for Lewy pathology | This correlation was more marked in cases with moderate to high Aβ load | •Retrospective | ||
| Kalaitzakis et al. [27] | 2009 | 14 PDND16 PDD | α-synuclein, tau, and Aβ deposition in the caudate, putamen, and accumbens | α-synuclein and tau deposition were rare in the striatum in both groups | •α-synuclein immunostaining |
| Aβ burden was greater in the striatum of PDD than in PDND | |||||
| Compta et al. [28] | 2011 | 27 PDND29 PDD | Braak stages for α-synuclein and tau | Cortical Aβ+cortical Lew scores+Braak tau stages in combination predicted better dementia than each separately | |
| Semiquantitative Aβ plaques &CAA scores | Cortical Aβ scores &Braak tau stages, but not Lewy body scores or Braak α-synuclein stages, significantly correlated with MMSE scores | ||||
| Lewy densities and semiquantitative scores | High cortical Aβ score and older age at onset were associated with a shorter time-to-dementia period. | ||||
| Irwin et al. [29] | 2012 | 48 PDND92 PDD | Semiquantitative scores for neurofibrillary tangles, Aβ plaques &Lewy bodies/neurites | Cortical Lewy scores+APOE4 were the stronger correlates of dementia | |
| PDD+AD cases were older, had more Lewy pathology and CAA | |||||
| Kotzbauer et al. [30] | 2012 | 32 PDD | α-synuclein, tau &Aβ immunohistochemistry | Patients with synucleinopathy+Aβ had significantly shorter survival | |
| Sierra et al. [31] | 2016 | 10 PD10 PDD10 DLB10 AD10 controls | Semiquantitative scores for α-synuclein, Aβ and neurofibrillary tangles in the midbrain (substantia nigra &tectum)+cerebellum (for Aβ) | α-synuclein midbrain scores rose from controls to AD and then LBD irrespective of dementia | |
| Aβ and tau more prominent in the tectum increasing from controls to LBD (mostly dementia cases) then peaking in AD | |||||
| Cerebellar Aβ scores were marginal in the LBD-spectrum (as opposed to AD) only showing a trend towards greater involvement in dementia cases | |||||
| Irwin et al. [32] | 2017 | 213 LBD | Semiquantitative scores for neurofibrillary tangles, Aβ plaques &Lewy bodies/neurites | Greater Alzheimer pathology (chiefly of neurofibrillary type) implied higher α-synuclein scores and shorter time-to-dementia |
Aβ, amyloid-β; AD, Alzheimer’s disease; DLB, dementia with Lewy bodies; LBD, Lewy body disorder; PD, Parkinson’s disease; PDD, Parkinson’s disease dementia; PDND, Parkinson’s disease non-demented.