Current concepts and controversies in the pathogenesis of Parkinson’s disease dementia and Dementia with Lewy Bodies

Introduction

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases, characterised clinically by bradykinesia, rigidity and tremor. Pathologically, the cardinal features are of degeneration of dopaminergic cells in the nigrostriatal system, and by widespread intracytoplasmic Lewy bodies (LBs) and Lewy neurites (LNs)¹, the main component of which is α-synuclein². How Lewy pathology relates to dopaminergic degeneration and later to more widespread cell death has remained contentious^3,4.

Whilst for many years PD was considered a movement disorder, in recent years a wide range of non-motor features, including cognitive impairment, have increasingly been recognised. Although subtle cognitive impairment is relatively common even at the point of diagnosis, after ten years of symptoms the population prevalence of frank dementia (so-called Parkinson’s disease dementia, or PDD) may be as high as 70%⁵. Conversely, patients with dementia with Lewy bodies (DLB) have cognitive impairment that precedes or coincides with the development of parkinsonian signs by a (arbitrary) year or more⁶. While the precise pathophysiological mechanisms that lead to PDD and DLB are not fully understood⁷, neuropathologically they are difficult to differentiate^8–10, apart from a higher prevalence of Alzheimer’s-like pathology in DLB than PDD^11,12. In many ways, PDD and DLB are widely considered to be either end of a spectrum of one disease^9,13. Considering the two diseases together as a joint entity of PDD/DLB provides a means of determining common mechanisms leading to the same end-point, and any differences potentially provide additional insights into phenotypic diversity (Table 1).

Although pathological markers of PDD/DLB are now well established, several key areas have until recently remained relatively less well explored. These include the pathophysiological processes that underpin PDD/DLB; mechanisms of cellular toxicity; and how the disease progresses within the brains of people affected by PDD/DLB. In addition, robust models to explain why specific brain regions or even certain neurons are more prone to involvement in PDD/DLB have been lacking, as has an understanding of the mechanisms underlying heterogeneity between individuals with PDD/DLB, including the timing of onset of cognitive decline.

Here, we review recent advances that offer new insights into these questions and shed light on the pathogenesis of PDD/DLB under five headings: (1) We review evidence that other macromolecular structures, and not just LBs, have a role in the neurodegeneration of PDD/DLB; (2) we consider recent challenges to the primacy of LBs themselves in causing cell death and dementia; (3) we consider theories for progression of pathology within individuals with PDD/DLB; (4) we examine aspects of cellular morphology and physiology that confer vulnerability to Parkinson’s pathology; and (5) we consider the role of genetic factors in the pathogenesis of sporadic PDD/DLB and what insights these provide in furthering our understanding of these diseases.

Not just Lewy bodies

The neuropathological signatures of PD, PDD and DLB were first described by Friedrich Heinrich Lewy¹. He observed large eosinophilic spherical or kidney-shaped inclusions in neuronal cell bodies that were later termed Lewy bodies (LBs) (Figure 1). He also described structures that stained less easily with acidophilic dyes and varied in morphology between short and thick or long and thread-like which were subsequently termed Lewy neurites (LNs). Immunohistochemical techniques that stained for ubiquitin¹⁴ and later the use of anti-α-synuclein antibodies² revealed the extent of α-synuclein deposition in the LBs and LNs in PDD/DLB. Lewy described their occurrence in patients with paralysis agitans in various brain structures, including, but not primarily, in the substantia nigra (SN), with a diffuse and cortical distribution¹⁵. Little clinical detail was given in his first descriptions, and only later was the association with dementia fully recognised and described as DLB or “diffuse Lewy body disease”^16,17.

Figure 1. Alpha-synuclein pathology.

(a) Lewy body found in the dopaminergic cells of the substantia nigra (double arrow) along with Lewy neurites (arrows). (b) Lewy bodies observed in the cingulate gyrus (arrows). (c) A dense network of Lewy neurites in the CA2 subregion of the hippocampus. Bar = 50 µm (a) and 100 µm (b, c).

Since then, evidence has been accumulating that other pathologies are also present in patients with PD and dementia and that it is the combination of pathologies that is important for determining cognitive impairment in the face of Parkinson’s pathology. Thus, the combination of Lewy pathology and Alzheimer’s disease (AD) pathology (fibrillary β-amyloid and intraneuronal tangles consisting of hyperhosphorylated tau) predicts dementia in PD better than the severity of any single pathology¹⁸; and in clinical studies in patients with newly diagnosed PD, cerebrospinal fluid (CSF) biomarker evidence for β-amyloid pathology (for example, low concentrations of Aβ1-42) is a significant predictor of subsequent cognitive impairment¹⁹.

Large-scale studies comparing patterns of CSF biomarkers between patients with DLB and PDD show that lower levels of Aβ1-42 (combined with higher tau levels) are associated with DLB rather than PDD and are seen particularly in patients with more rapid dementia^20–22. CSF Aβ1-42 is inversely related to brain density of amyloid plaques²³ and therefore lower CSF Aβ1-42 concentration is supportive of higher brain amyloid in these patients. Similarly, in positron emission tomography imaging studies using amyloid radioligands, higher levels of amyloid are seen in patients with DLB than PDD and in PD patients with more rapid cognitive progression^24–26. Patients with the combination of Lewy-related pathology and evidence for brain β-amyloid accumulation have a more aggressive disease course and have shorter survival times and higher incidence of cognitive dysfunction even compared with pure AD^27–31, and these proteins may mutually promote each other’s aggregation³². Thus, in a large retrospective study, Irwin and colleagues⁸ showed a strong correlation between the extent of neurofibrillary tangles, neuritic plaques and α-synuclein, suggesting synergistic effects of AD and α-synuclein pathology. Patients with PDD/DLB with more cortical β-amyloid plaques also have more cortical α-synuclein aggregates^33,34. Conversely, even in “pure” young-onset familial (autosomal dominant) AD, a high proportion of patients have LB pathology at autopsy (although in these cases it tends to localise to the amygdala)^35,36 and α-synuclein accumulates within amyloid plaques of dystrophic neurites³⁷. This synergy is also seen in mouse models of PDD/DLB: transgenic mice overexpressing both human β-amyloid and α-synuclein have higher levels of LB pathology and greater memory deficits than mice expressing just α-synuclein³⁸; and double transgenic mice overexpressing two AD-related genes (amyloid precursor protein and presenilin 1) have greater amounts of α-synuclein as well as β-amyloid than mice transgenic for one mutation alone³⁹.

A potential mechanism for this synergy is through phosphorylation. α-synuclein can induce tau hyperphosphorylation^40,41, thereby promoting neurofibrillary tau tangle formation^41,42. Similarly, in PDD/DLB, the main modification of α-synuclein is Ser129 phosphorylation⁴³. An estimated 90% of α-synuclein in LBs and LNs is phosphorylated at Ser129, compared with only 4% in unaffected brains⁴⁴. This changes its solubility and enhances the tendency for α-synuclein aggregation. Higher levels of phosphorylated α-synuclein are seen at earlier stages of PDD/DLB than LB pathology⁴⁵, and phosphorylated α-synuclein levels correlate with disease severity^46,47. Recently, Swirski and colleagues⁴⁸ shed light on the synergistic relationship between β-amyloid and α-synuclein, demonstrating correlations between phosphorylated Ser129 α-synuclein and the amount of β-amyloid and between the proportion of α-synuclein phosphorylated at Ser129 and antemortem cognitive function. Importantly, by taking cells that overexpressed α-synuclein, exposing them to toxic forms of β-amyloid (Aβ1-42) and showing that this led to a higher proportion of α-synuclein phosphorylated at Ser129, they were able to show a causative role for β-amyloid in pathological synuclein phosphorylation. Taken together, these studies show that the synergistic relationship between AD pathology and α-synuclein is bidirectional and that each protein synergises the other.

Not even Lewy bodies

Although Lewy bodies are considered the neuropathological signature of PD, the severity of clinical symptoms, disease duration, and presence of cognitive decline or visual hallucinations (core features of PDD/DLB) do not correlate with LB density^3,49–51; and in some patients with PDD, no LBs are seen in cortical regions or even outside the brainstem⁵². A recent neuropathological study showed that cell loss can precede LB accumulation⁵³, calling into question the hypothesis that LBs are the toxic agents in PD that drive neurodegeneration⁵⁴. One proposed explanation is that it is the precursors of LBs (which cannot be seen by light microscope), rather than the LBs themselves, that precipitate neurodegeneration⁵⁵. Although there is no correlation between LB and nigral neuronal loss, there is a correlation between neuronal loss and total α-synuclein aggregate burden^56,57; and evidence suggests that initial amorphous α-synuclein deposits known as pale bodies and pale neurites may mediate cell damage and later evolve into more aggregated LBs⁵⁵.

A related theory proposes that neurodegeneration and cell death are not caused by LBs but that instead LBs provide protection from α-synuclein aggregates^58,59. In this way, LBs and LNs may be an indirect indicator of disease but do not reflect the full extent of neurodegenerative pathology⁶⁰, similar to that proposed for β-amyloid plaques in AD^61,62.

The recent discovery of different strains of α-synuclein is an intriguing potential explanation for the heterogeneity of synucleiopathies between individuals⁶³. Bousset and colleagues generated two distinct high-molecular-weight assemblies of α-synuclein: one with a cylindrical and fibrillar structure and one with a more flat and ribbon-like structure, as shown by transmission electron microscopy and x-ray diffraction⁶³. Crucially, the fibrillar conformation was more toxic to cells, inducing caspase-3 activation and reactive oxygen species and showing a higher propensity to bind and penetrate cells. Moreover, the two strains showed differential abilities to induce tau aggregation both in cultured neurons and in vivo⁶⁴ (and see review⁶⁵). Thus, and again in line with proposed models for AD, pathological processes upstream of the Lewy bodies may be more influential in disease progression, and more aggressive disease may relate to distinct strains of α-synuclein.

Not “prion-like” spread?

Braak and colleagues proposed that Lewy pathology could spread from cell to cell in a manner similar to the proposed spread of prion proteins. This followed detailed observations that patients who had died at earlier clinical stages of PD had Lewy pathology confined to the lower brainstem but that those patients who succumbed at later stages of disease had more abundant Lewy pathology in the upper brainstem and then cortex^66,67. The authors hypothesised that the disease started in the brainstem before spreading into the striatum and then the cortex⁶⁸; and more recent work has suggested disease originating in the gut and nose^69–71. This model gathered support when foetal tissue grafts transplanted into human striatum were found to show Lewy-like inclusions within decades of transplantation⁷². A series of investigations followed, aimed at showing transmission of α-synuclein between cells. In cellular models, transfection of α-synuclein precursors into cells expressing α-synuclein induced Lewy body–like inclusions^73,74. In mice, synthetic α-synuclein fibrils were shown to spread from the site of injection to synaptically connected structures, creating Lewy-like pathology^75,76. Similar observations were made when young mice were injected in various brain regions with extracts from the brains of older motor-impaired mice⁷⁷.

However, these and other studies do not yet provide incontrovertible evidence that α-synuclein induces pathology or even spreads between cells. Not all cases find Lewy-like inclusions in transplanted tissue⁷⁸ and some find them in only a minority of grafted cells⁷⁹. The concentrations of α-synuclein precursors in cellular models are typically above physiological levels of α-synuclein⁸⁰; and in animal models, factors other than α-synuclein itself could be promoting α-synuclein aggregation, including damage from injection sites or local inflammation⁸⁰. Indeed, more detailed analysis of one animal model revealed that the α-synuclein inclusions appeared randomly without any evidence of spread between cells⁸¹.

For a mechanism involving trans-synaptic spread, it would be expected that cells with the greatest synaptic connectivity to regions affected in early PD would be at greatest risk of developing Lewy pathology. However, this is not the case; mouse studies show that regions with strong connectivity to the SN do not show the most abundant Lewy pathology⁸² (see also 83).

Instead, theories are emerging to suggest that Braak and colleagues’ observations of a stereotypical pattern of involvement of particular brain regions with disease severity (inevitably based on extrapolation from cross-sectional pathological observations) reflect selective vulnerabilities of specific cells that tend to be affected first in PD^80,83,84, rather than the physical transmission of a pathological agent. It is also possible that the pattern of “spread” reflects a combination of processes: with cell-to-cell propagation starting in response to injury or inflammation, at particular sites and affecting particular neuronal populations, before spreading through networks of similar cells that are similarly vulnerable⁸⁵.

Indeed, it is these selective vulnerabilities and the pattern of involvement that may reflect the heterogeneity across the spectrum of PDD/DLB. Many of the cells affected in PD are key neurons in the neuromodulatory control networks. These share several notable traits: they are all characterised by long and highly branched axons and a large number of transmitter release sites. New models propose that it is these common features that predispose particular neurons to be affected early in PD: we next examine the evidence for each of these in turn.

Cell vulnerabilities

Genetics

The genetic underpinnings of PDD/DLB have been vastly understudied. Two main reasons may have contributed to this: first, the fact that large, homogeneous cohorts of PDD/DLB cases have been difficult to assemble and thus large-scale genetic studies have not been possible; second, because we do not tend to see familial aggregation of DLB, as we do in some instances in PD or AD, the general reasoning has been that there is no genetic basis for this disorder. However, the last few years have started to shift this notion, much like the early ’90s did for PD and the early ’70s for AD.

One of the first hints that genetics played a role in DLB came from the study of GBA. Homozygous mutations in GBA are known to cause a lysosomal storage disorder (Gaucher disease), whereas the same mutations when heterozygous increase risk for PD¹²⁰. In DLB, a similar effect of these mutations was identified¹²¹. The immediate suggestion from these data is that there is an identical underlying lysosomal dysfunction occurring in both diseases. More recently, an association study showed that common variability is also involved in DLB. Variants at the APOE and SNCA loci were shown to be associated with DLB in a cohort of approximately 800 cases¹²². Interestingly, whereas the APOE association was identical to the one seen in AD, the association at SNCA was completely independent of the one seen in PD. These results suggest that, although the same locus is involved in both diseases, the way in which this involvement occurs is different. It is tempting to speculate that perhaps the differential association underlies differential gene expression of SNCA, potentially in a tissue-specific manner.

It was also shown that, in addition to sharing two loci of association with PD and AD, there is a substantial amount of genetic correlation between DLB and both PD and AD¹²³ and that the heritability of DLB can be estimated to be approximately 30%, similar to estimates for PD¹²⁴.

Taken together, these data strongly suggest not only that DLB has a genetic component but also that this component has a unique architecture when compared with PD and AD leading to the specific phenotype of DLB. The genetic differences between PDD and DLB have, so far, not been studied in detail. In PDD, factors that predispose to earlier dementia may have some genetic underpinnings. For example, REM sleep behaviour disorder, which is predictive of cognitive involvement when it occurs in patients with PD¹⁹, is more common in patients carrying GBA¹²⁵ and SNCA mutations^126,127 and less common in patients carrying LRRK2 mutations¹²⁸.

However, the recent genetic data described above suggest that categorising diseases in a binary fashion might not be adequate and that it is the varying polygenic characteristics between individuals that underpin heterogeneity in patients with PDD/DLB.

As our understanding of these factors increases, these concepts will increasingly be included in our thinking of disease pathobiology; and as we move to an era of personalised medicine, genetic risk is likely to be used diagnostically and to predict which patients with PD pathology are at risk of developing cognitive impairment, perhaps replacing the arbitrary clinical criteria that are currently used to distinguish DLB from PDD.

Summary

Recent cellular, animal, post-mortem and genetic studies are beginning to shed light on key and previously unknown aspects of the pathophysiological mechanisms that underlie PDD/DLB. These include insights into which aspects of PD pathology are most closely linked to cognitive decline, the interaction between AD and PD pathology, and the cellular and morphological features that may explain disease spread and selective neuronal vulnerability. Although genetic studies of DLB/PDD are in their infancy, results to date show commonalities with both PD and AD but also notable differences. As our understanding of the basic pathophysiology of these conditions expands and as links between genotype, pathological mechanisms and phenotype are established, prospects for personalised medicine will increase: these include prediction of not only which patients will develop cognitive impairment but when. Importantly, these observations may also provide important insights into the mechanisms underlying neurodegenerative diseases more generally as well as new targets for novel disease-modifying therapy to prevent dementia in PD and DLB.

Abbreviations

AD, Alzheimer’s disease; CSF, cerebrospinal fluid; DLB, dementia with Lewy bodies; LB, Lewy body; LN, Lewy neurite; PD, Parkinson’s disease; PDD, Parkinson’s disease dementia; SN, substantia nigra.