Dementia with Lewy bodies

Olivia Salthouse, Jenny Bradshaw and Michael Saling

Introduction

As the first and second most prevalent causes of dementia, Alzheimer disease dementia (ADD) and dementia with Lewy bodies (DLB) lie at opposite ends of what can be called, for want of a better term, a temperamental spectrum. ADD, at least in its earlier stages, is a quiet dementia. Patients present with a muted complaint of memory ditficulties, tending to withdraw and listen when conversation demands more of their failing memory and language than they are able to retrieve. As the condition progresses, the scene is one of devastating cognitive loss, without overt and predominating excessive states or behaviours. Sensation and movement are preserved well beyond the advent of memory failure. Its underlying pathology, tauopathy in particular, causes massive neuronal loss and cerebral atrophy.

DLB, on the other hand, is a tumultuous condition. Its presentation is peppered with fluctuations that can range from inaccessibility, through to confusion, to muddlement, with hallucinations, delusional constructs, misrecognition of family members and friends, and sleep disturbances in which dreams are floridly acted out. Movement can be affected by fragments of what was once called paralysis agitans, in other words, parkinsonism. Sometimes there is a transient loss of consciousness, falling, and syncope. Memory' loss is not an early feature, and while it progresses, it does not reach the relatively early amnestic proportions seen in ADD. Neuronal loss and cerebral atrophy are not as severe as that seen in ADD, but metabolic ups and downs go a long way to explain the clinical picture.

In this chapter, we explore the fluctuating nature of DLB as it manifests across multiple systems, with a particular emphasis on the relationship between sleep and wakefulness as a basis for aspects of the symptomatic landscape.

A brief epidemiology of dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is considered to be the second most common form of dementia after dementia of the Alzheimer’s type (DAT; Bonanni et al., 2008; Cromarty' et al., 2016; Terzaghi et al., 2013). While some parallels can be drawn between DLB and DAT, the cardinal clinical and pathologic features of DLB are largely distinct (McKeith, 2002). DLB was initially conceptualised as a Lewy body variant (LBV) of DAT (McKeith, 1998, 2002; McKeith, Perry', Fairbairn, Jabeen & Perry', 1992), but continued research and clinical work within this area has, over recent decades, established DLB as a separate and distinct diagnostic entity (McKeith et al., 1996, 2005). It has been estimated that in older populations, DLB accounts for 10-15% of all dementias (McKeith, 2006); some estimates are as high as 25% (Mayo & Bordelon, 2014).

While early reports of Lewy body pathology' date back to 1912 (McKeith, 1998), DLB has been recognised as a specific and distinct dementia subtype for just over two decades. The first operational criteria were published in 1992 (McKeith et al., 1992), followed shortly thereafter by the first diagnostic criteria (McKeith et al., 1996). These have been updated more recently to incorporate ongoing research, an increased evidence base, and a greater clinical understanding of the disease (McKeith et al., 2005, 2017).

Neuropathology

Pathologically, DLB is characterised by the presence of Lewy bodies (Kaplan, Ratner & Haas, 2003; McKeith, 2002). Lewy bodies, a hallmark feature, are distributed throughout the cortex, typically in temporal, frontal (with an emphasis on the cingulate region), parietal, and occipital cortices (Usman, Oskouian, Loukas & Tubbs, 2017). They are also found in the brain stem and autonomic structures, a-syrmclein is the core constituent of Lewy bodies, uniting DLB with Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), and multiple system atrophy (MSA) (the a-synyucleinopathies) at a molecular level (Spillantini et al., 1997). A neuritic pathology has also been implicated (McKeith et al., 2004), along with a significant acetylcholine deficit (ibid.), the latter being more severe than that documented in Alzheimer’s disease (AD). Neuritic features are common in the hippocampus (predominantly in the CA 2 and CA 3 regions, anatomically unlike the pattern of tau deposition in AD), parahippocampal gyrus and amygdala (Usman et al., 2017).

Foguem and Manckoundia (2018) have postulated a spectrum ranging from the a-synyucleinopathies to the tauopathies (such as Alzheimer’s disease and frontotemporal dementia), because of the extent to which these proteinaceous misaggregations overlap. In most cases with a clinical diagnosis of DLB, the Lewy body and neuritic pathology is accompanied by sparse Alzheimer pathology, which does not declare itself as an Alzheimer-type dementia at a clinical level, but might have an independent etfect on cognition in DLB. Molecular neuroimaging points increasingly to the heterogeneity of DLB pathology, as well as to the possibility that a-synucleinopathy and Ap-amyloidopathy, despite its low levels, might interact synergistically to increase dysfunction (Bohnen, Muller & Frey, 2017; Sarro et al., 2016). Cases with ‘pure’ Lewy pathology are rare (Gurd et al., 2000).

Cortical atrophy is generally less severe and extensive in DLB than in AD (Watson, O’Brien, Barber & Blamire, 2011). Grey matter atrophy in DLB is predominantly found in temporal, parietal, occipital, and subcortical structures relative to normal controls, and there is less mesial temporal atrophy than is typically found in AD (Watson et al., 2011). Occipital grey matter atrophy is less pronounced than it is in other parts of the cerebral hemisphere. Glucose uptake in the medial and lateral occipital lobes (despite the relative scarcity of occipital Lewy bodies) is significantly lower than in AD, but posterior cingulate uptake is higher (Lim et al., 2009), resulting in the ‘cingulate island sign’ on FDG PET (ibid.). This is characterised by a visually prominent posterior cingulate region against a background of low bilateral medial occipital uptake, and is highly sensitive and specific in differentiating DLB from typical onset AD (Lim et al., 2009; Sawyer & Kuo, 2018). It is worth emphasising the fact that the severe occipital metabolic defect in DLB is not accompanied by a commensurate degree of atrophy (Iaccarino et al., 2018), because it relates to the special role that metabolic factors and synaptic dysfunction play in DLB symptoms, and ultimately, early detection.

 
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