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Epidemiology, pathology, and pathogenesis of dementia with Lewy bodies

Epidemiology, pathology, and pathogenesis of dementia with Lewy bodies
Literature review current through: Jan 2024.
This topic last updated: Jul 14, 2021.

INTRODUCTION — Dementia with Lewy bodies (DLB) is one of the most common causes of dementia after Alzheimer disease (AD) and vascular dementia. DLB often presents a diagnostic challenge given this clinical heterogeneity and overlap with other neurodegenerative diseases. Further, it was initially often overlooked pathologically because of the difficulty in identifying cortical Lewy bodies with routine histochemical stains. With the advent of immunohistochemical stains for constituents of Lewy bodies, the prevalence of this disorder has been better characterized. However, challenges still remain in defining and diagnosing DLB as an entity distinct from other degenerative dementias.

DLB has been given various names over the years, which in part reflects the uncertainty as to whether it is one of several distinct disease entities with the shared common finding of cortical Lewy bodies, or represents one point on a spectrum of Lewy body disease. Names by which it has been called include diffuse Lewy body disease, Lewy body dementia, Lewy body variant of AD, cortical Lewy body disease, and senile dementia of the Lewy body type. More recently there has been an effort to apply the term "Lewy body disease" as a collective description of the various entities characterized pathologically by Lewy body formation (Parkinson disease [PD], PD dementia [PDD], and DLB), the terms "diffuse Lewy body disease" and "neocortical Lewy body disease" to describe the finding of Lewy bodies in neocortical neurons, and the term "DLB" to describe the clinical syndrome.

This topic will describe the epidemiology, neuropathologic findings, and potential pathogenic mechanisms of DLB. Clinical features, diagnosis, prognosis, and treatment are discussed separately. (See "Clinical features and diagnosis of dementia with Lewy bodies" and "Prognosis and treatment of dementia with Lewy bodies".)

INCIDENCE AND PREVALENCE — DLB, although once considered rare, is recognized as a common cause of neurodegenerative dementia, affecting up to 5 percent of the general population and accounting for as much as 30 percent of all dementia cases [1,2]. Such prevalence estimates place DLB as one of the most common causes of dementia, superseded only by Alzheimer disease (AD) and vascular dementia. Incidence rates have been estimated at 0.1 percent per year in the general population but up to 3.2 percent for new dementia cases [1].

Similar to other neurodegenerative diseases, the prevalence of DLB increases with age [3], with an average age at presentation of 75 years [4]. DLB has been reported to occur more frequently in males, with a male-to-female ratio of 4:1 [5]. However, a separate study showed an increased prevalence of Lewy body pathology in females compared with males [6].

PATHOLOGY

Gross pathology — DLB is associated with nonspecific gross pathologic changes of the brain that overlap with other neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson disease (PD) [7]. The cortical atrophy is typically less marked than AD but follows a similar pattern, involving frontal, temporal, and parietal lobes, with relative sparing of occipital cortex. Limbic structures, such as the amygdala and cingulate gyrus, however, can show severe atrophy. Similar to PD, the substantia nigra and the locus coeruleus can show variable degrees of pallor.

Microscopic pathology — The microscopic pathologic hallmark of DLB is the presence of Lewy bodies throughout the neocortex as well as in the brainstem nuclei and limbic structures [8,9]. On hematoxylin- and eosin-stained sections, these round, eosinophilic, cytoplasmic inclusions can be seen readily in pigmented neurons within the substantia nigra and locus coeruleus but are less easily visualized in cortical neurons [10]. Immunohistochemical staining for alpha-synuclein [10], as well as p62 (a protein of the nuclear envelope that colocalizes with ubiquitin-tagged proteins) and ubiquitin [11], can aid in the identification of Lewy bodies, particularly outside the brainstem nuclei (picture 1A-B). Cerebral cortical Lewy bodies are often localized to small neurons in the deep cortical layers and typically involve the temporal cortex, followed by the parietal and frontal cortex.

In addition to Lewy bodies, Lewy neurites are also visualized with the aid of alpha-synuclein immunohistochemistry [10]. These elongate, beaded nerve processes are found in the CA2 and CA3 regions of the hippocampus, the transentorhinal cortex, the nucleus basalis of Meynert, amygdala, dorsal vagal nucleus, and other brainstem nuclei.

Superficial microvacuolation of cerebral cortex, especially temporal cortex, is another feature noted in some cases and may be related to disease severity [12].

Up to 80 percent of patients with DLB will have concomitant AD neuropathologic change [13-15]. Often the AD changes are less severe than in cases of AD dementia without Lewy bodies, particularly with respect to the extent of neurofibrillary degeneration [16]. AD pathology is described in detail separately. (See "Epidemiology, pathology, and pathogenesis of Alzheimer disease", section on 'Pathology'.)

CLINICOPATHOLOGIC CORRELATION — A number of studies have attempted to characterize the relationship between Lewy body quantity or distribution and symptoms, and this has generally proven to be challenging.

In one pathologic series, the overall density of Lewy bodies correlated with the severity of cognitive impairment, independent of other neuropathologic changes [17]. However, in another series, individuals with pure DLB had only moderate cognitive impairment, regardless of the extent of neocortical Lewy bodies [18].

Others have demonstrated an association between the localization and density of Lewy bodies with other clinical symptoms, such as visual hallucinations with increased numbers of Lewy bodies in the anterior and inferior temporal lobe [19], as well as dysautonomic symptoms with Lewy bodies in the spinal cord intermediolateral cell column, hypothalamus, and dorsal vagal nuclei [4,20]. However, a robust relationship between Lewy bodies and the fluctuating cognition characteristic of DLB has not been demonstrated. In some cases, Lewy neurites and neurotransmitter deficits appear to associate better with some of the clinical symptoms than Lewy bodies [21,22]. Others have observed that, compared with controls, there is marked loss of dopaminergic neurons in the periaqueductal gray area of the midbrain in DLB, which is thought to correlate with the observation that some patients with DLB have excessive daytime sleepiness [23].

The presence of concomitant Alzheimer disease (AD) neuropathologic change is thought to modify the clinical presentation and makes such cases difficult to differentiate clinically [24]. For example, some studies have shown that the presence of high-stage neurofibrillary degeneration is associated with a clinical presentation more similar to AD with increased severity of cognitive impairment and older age at presentation [25,26]. However, other studies suggest that the degree of AD and Lewy body pathologic changes are independent of one another and that both are independently associated with severity and duration of dementia [27].

There is significant overlap and convergence of the clinical presentation of DLB and Parkinson disease dementia (PDD), which are distinguished primarily by the temporal sequence of clinical characteristics [28]. Similarly, the neuropathologic features of DLB and PDD are similar, including Lewy bodies in cortical, limbic, and subcortical brainstem regions. Although there are some distinguishing trends in the neuropathologic features of DLB and PDD, including increased prevalence and extent of concomitant AD neuropathologic changes in DLB and differences in Lewy body distribution and severity, both are highly variable and it is unreliable to attempt to distinguish one from the other on pathologic features alone. The clinical features of DLB and PDD are described in detail separately. (See "Clinical features and diagnosis of dementia with Lewy bodies", section on 'Clinical features' and "Cognitive impairment and dementia in Parkinson disease" and "Cognitive impairment and dementia in Parkinson disease", section on 'Clinical features'.)

There are also cases in which neocortical Lewy bodies are identified but there is no clinical history of dementia. This apparent resilience to the presence of Lewy bodies is poorly understood but may represent a preclinical phase of Lewy body disease [29].

PATHOPHYSIOLOGY

Alpha-synuclein – Aggregated alpha-synuclein is a key component of Lewy bodies and Lewy neurites [30].

Alpha-synuclein is expressed throughout the brain and is localized at presynaptic terminals [31,32]. Its function is not entirely understood but is believed to play a role in neurotransmitter release and vesicle turnover [33]. Under pathologic conditions, such as elevated oxidative stress, alpha-synuclein undergoes a structural change from its natively unfolded state to form oligomers and protofibrils, and ultimately beta sheet structures that organize and deposit as Lewy bodies [8,33]. It is not known whether Lewy bodies and Lewy neurites are themselves neurotoxic, whether they are bystanders in the disease process, or whether they represent an attempt to limit injury from the neurotoxic alpha-synuclein oligomers.

Cell type susceptibility and dysfunction – Dopaminergic neurons appear to be more susceptible to alpha-synuclein dysfunction and Lewy body formation, which may be due to the fact that these neurons have a greater need for alpha-synuclein [34]. There is evidence that alpha-synuclein may play a role in dopamine metabolism by modulating the activity of tyrosine hydroxylase and reducing its ability to hydroxylate tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA) [35]. Alpha-synuclein may also regulate the activity of the dopamine transporter (DAT), reducing the reuptake of dopamine back into dopaminergic nerve terminals [36].

There is also significant cholinergic neuronal loss and severely depleted choline acetyltransferase (ChAT) levels early in DLB [37,38]. Reduced cortical levels of ChAT have been associated with the presence of hallucinations [37-39]. In two patients, marked reduction in ChAT activity identified postmortem appeared to correlate with a clinical response to cholinesterase inhibitors during life [37]. Thus, cholinergic depletion appears to be an important factor in the symptoms of early DLB, at least in some patients. Increased density of postsynaptic muscarinic acetylcholine receptors has also been reported in DLB and associated with delusions [39,40].

Regional susceptibility and spread – Lewy body disease has been staged based on the apparent order of progression, beginning with the lower brainstem or olfactory bulb, spreading rostrally to the substantia nigra, then into the limbic areas, and finally involving the neocortex [41]. There is some evidence that alpha-synuclein propagates trans-synaptically to contribute to the anatomic spread of Lewy bodies [42,43]. This theory is supported by in vitro and in vivo studies that demonstrate the endocytosis of extracellular oligomeric aggregates as well as the transmembrane translocation of monomeric alpha-synuclein [44-46]. Additionally, studies from patients with Lewy body disease who received healthy embryonic neuron grafts have revealed that approximately five years post-transplant, neurons within the graft developed Lewy bodies [47,48].

Animal and cell models – There are a number of mouse models for Parkinson disease (PD), and motor deficits have been better studied than cognitive deficits in these models of alpha-synuclein overexpression [49,50].

However, there are some rodent models that produce reliable cognitive deficits and can provide end-point measures to test new therapies for DLB [51]. Similar to DLB in humans, these models show predominantly cerebral cortical and hippocampal Lewy body formation with associated deficits in hippocampal function.

In addition to animal models, there are several different cellular models that are increasingly being used to study DLB and other synucleinopathies. Seeding primary neuron cultures with alpha-synuclein fibrils is a model that recapitulates many of the key structural and biochemical features of Lewy body pathogenesis [52]. Point mutations can also be genetically engineered into human pluripotent stem cells to help understand the temporal and cell-type specific regulation of alpha-synuclein and ultimately to screen for potential therapeutic targets [53,54].

Therapeutic targets – There are currently no disease-modifying therapies for DLB, but there are several agents currently in clinical trials [55]. While previous therapeutic targets were focused on symptomatic relief, disease-modifying therapies have more recently been under investigation.

Given the human, animal, and cell model data implicating alpha-synuclein aggregation in the manifestation and progression of DLB, therapeutic strategies have focused on reducing alpha-synuclein levels in the brain [56]. These include immunization with antibodies that recognize abnormal alpha-synuclein and promote its degradation, alpha-synuclein gene knockdown with viral vector-based RNA interference strategies, and small molecule and peptide inhibitors of alpha-synuclein. These strategies are still experimental, and at present, the only treatment options for patients are those aimed at symptom relief by increasing dopaminergic and cholinergic neurotransmission. (See "Prognosis and treatment of dementia with Lewy bodies", section on 'Treatment'.)

PREDISPOSING FACTORS

Genetics — Although DLB is considered to be mostly a sporadic, late-onset disease, there have been a number of DLB families described in the literature. In addition, a DLB genome-wide association study (GWAS) has provided evidence that genetic factors play an important role in the pathogenesis of both familial and sporadic forms of DLB, accounting for up to 60 percent of disease susceptibility [57,58].

Mutations in some genes appear to play a causal role in DLB pathogenesis while others modulate disease risk. Importantly, the genes implicated in DLB have also been associated with other neurodegenerative diseases [59], as described below, while genes specific to DLB have yet to be identified [60].

SNCA: The gene encoding the alpha-synuclein protein has been implicated in both Parkinson disease (PD) and DLB [61]. Several point mutations have been identified but are relatively rare and result in a diverse phenotypic spectrum ranging from PD, to PD dementia (PDD), to DLB as well as multiple system atrophy (MSA) and frontotemporal dementia (FTD). Even within families there is a wide variety of disease expression, and some mutations are not fully penetrant. The role of mutations in this gene is not clear, but some appear to increase the propensity for aggregation of the alpha-synuclein protein while others may perturb its membrane-binding ability. Mutations in the other members of the synuclein family (beta-synuclein and gamma-synuclein) have also been identified and may play a role in the processes that lead to DLB [62]. SNCA in PD and MSA is discussed separately. (See "Epidemiology, pathogenesis, and genetics of Parkinson disease", section on 'SNCA-associated PD' and "Multiple system atrophy: Clinical features and diagnosis".)

APP: Mutations in the amyloid precursor protein gene have long been associated with Alzheimer disease (AD) and have more recently been linked to DLB. For example, duplication of APP was reported in a family with autopsy-confirmed DLB [63], and to date, 53 percent of autopsies performed on individuals with the APP717 mutation have revealed the presence of Lewy bodies, suggesting a direct link between APP and Lewy body formation [64,65]. The role of amyloid precursor protein gene in AD is discussed separately. (See "Genetics of Alzheimer disease", section on 'Amyloid precursor protein'.)

PSEN1/PSEN2: Point mutations in the presenilin genes are another example of important causes of familial AD that also have been linked to DLB. Presenilins are key components of the gamma-secretase complex involved in the processing of amyloid, and it has been hypothesized that these mutations, which result in increased levels of beta-amyloid, may provide an environment conducive to Lewy body formation [66]. Specifically, the p.DT440 point mutation in PSEN1, which has been reported in a patient with combined clinical and pathologic features of DLB/AD [67], has been shown to enhance Ser129 phosphorylation of alpha-synuclein [68]. The role of presenilins in AD is discussed separately. (See "Genetics of Alzheimer disease", section on 'Presenilin 1' and "Genetics of Alzheimer disease", section on 'Presenilin 2'.)

MAPT: Mutations in the microtubule-associated protein tau gene are associated with tauopathies such as FTD, but more recently, mutations in this gene have been linked to the pathologic changes of DLB and may play a role in promoting the aggregation of alpha-synuclein [69]. The role of this gene in FTD is discussed separately. (See "Frontotemporal dementia: Epidemiology, pathology, and pathogenesis", section on 'MAPT mutations'.)

GBA: Homozygous mutations in the glucocerebrosidase gene cause Gaucher disease. The observation that some patients with Gaucher disease also had parkinsonian features led to studies showing that heterozygous variants in GBA can predispose to PD and DLB [70-72] (see "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Genetics'). Mutations in GBA result in reduced activity of beta-glucocerebrosidase, a lysosomal enzyme, which has been shown to impair degradation of alpha-synuclein within the lysosome, leading to its accumulation [73].

The reported frequency of GBA mutations ranges from 4 to 28 percent in cohorts of patients with DLB [71,74]. The frequency was even higher (31 percent) in a study of patients with DLB who were of Ashkenazi descent, a population with a high carrier rate of GBA mutations [75]. In this population, the presence of a GBA mutation was associated with earlier disease onset (64 versus 69 years), as well as more severe motor and cognitive impairment, but similar median survival from the time of diagnosis (10.5 versus 9.2 years).

APOE: Similar to AD, the apolipoprotein E epsilon 4 (ε4) allele has been associated with increased risk of DLB, and the APOE ε2 allele with decreased risk of DLB [76-78]. (See "Genetics of Alzheimer disease", section on 'Apolipoprotein E'.)

In a cohort that included 667 pathologically confirmed DLB cases and 2624 controls, APOE was confirmed as a strong risk factor for DLB [79]. This association remains even in the absence of AD, suggesting that APOE is related to DLB in a manner unrelated to the amyloid cascade.

CNTN1: One genome-wide association study in DLB provided evidence of a novel candidate locus, contactin 1 (CNTN1; rs7314908) [57]. CNTN1 encodes for the contactin 1 protein, a neuronal membrane protein that functions as a cell-adhesion molecule with a role in axonal function [80,81].

Acquired risk factors — Although genetic factors are an important component of DLB, the incidence of DLB is generally discordant among monozygotic twins [82], evidence that environmental or other epigenetic factors play an important role in the pathogenesis of DLB. While this has been extensively evaluated in PD, and a number of associations have been made, the same findings have not yet been reported in DLB, which may in part reflect the previous underrepresentation of DLB. One study in community-based cohorts found that traumatic brain injury with loss of consciousness is associated with neocortical Lewy bodies in addition to PD and parkinsonism [83]. Risk factors in PD are discussed separately. (See "Epidemiology, pathogenesis, and genetics of Parkinson disease" and "Cognitive impairment and dementia in Parkinson disease", section on 'Risk factors'.)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

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SUMMARY

Epidemiology Dementia with Lewy bodies (DLB), a clinical syndrome characterized by fluctuating cognitive impairment, dysautonomia, sleep disorders, hallucinations, and parkinsonism, is recognized as one of the most common causes of dementia accounting for as much as 30 percent of all dementia cases. (See 'Incidence and prevalence' above.)

Pathologic features – The pathologic hallmarks are Lewy bodies and Lewy neurites throughout the cortex best identified with the aid of alpha-synuclein immunohistochemistry. (See 'Microscopic pathology' above.)

Most patients with DLB will have some degree of Alzheimer-type pathology as well. (See 'Microscopic pathology' above.)

Pathogenesis – Aggregated alpha-synuclein is a key component of Lewy bodies and Lewy neurites. Dopaminergic neurons appear to be more susceptible to alpha-synuclein dysfunction. Cholinergic neuronal loss is also demonstrated and may be particularly important in the development of cognitive impairment in DLB. (See 'Pathophysiology' above.)

Genetic and other risk factors – Although there are relatively few examples of familial DLB and the majority are late-onset, sporadic cases, genetics appear to play an important role in both the pathogenesis and risk of DLB. (See 'Genetics' above.)

Environmental factors have been less well characterized than in Parkinson disease (PD); however, they are presumed to play a role in DLB as well. (See 'Acquired risk factors' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Ann Marie Hake, MD, and Martin R Farlow, MD, who contributed to an earlier version of this topic review.

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