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Dementia with Lewy Bodies: an Update and Outlook Tiago Fleming Outeiro1,2,3* , David J

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Dementia with Lewy Bodies: an Update and Outlook Tiago Fleming Outeiro1,2,3* , David J Outeiro et al. Molecular Neurodegeneration (2019) 14:5 https://doi.org/10.1186/s13024-019-0306-8 REVIEW Open Access Dementia with Lewy bodies: an update and outlook Tiago Fleming Outeiro1,2,3* , David J. Koss1, Daniel Erskine1, Lauren Walker1, Marzena Kurzawa-Akanbi1, David Burn1, Paul Donaghy1, Christopher Morris1, John-Paul Taylor1, Alan Thomas1,JohannesAttems1 and Ian McKeith1* Abstract Dementia with Lewy bodies (DLB) is an age-associated neurodegenerative disorder producing progressive cognitive decline that interferes with normal life and daily activities. Neuropathologically, DLB is characterised by the accumulation of aggregated α-synuclein protein in Lewy bodies and Lewy neurites, similar to Parkinson’s disease (PD). Extrapyramidal motor features characteristic of PD, are common in DLB patients, but are not essential for the clinical diagnosis of DLB. Since many PD patients develop dementia as disease progresses, there has been controversy about the separation of DLB from PD dementia (PDD) and consensus reports have put forward guidelines to assist clinicians in the identification and management of both syndromes. Here, we present basic concepts and definitions, based on our current understanding, that should guide the community to address open questions that will, hopefully, lead us towards improved diagnosis and novel therapeutic strategies for DLB and other synucleinopathies. Keywords: Dementia with Lewy bodies, Alpha-synuclein, Dementia, Alzheimer’s disease, Biomarkers Synucleinopathies: a general overview neurons and Lewy neurites (LN) in neuronal processes The synucleinopathies comprise several neurodegenera- [3]. The LBD comprise Parkinson’s disease (PD), Par- tive disorders characterised by the accumulation of ag- kinson’s disease dementia (PDD), and dementia with gregated forms of the protein α-synuclein (α-syn) in Lewy bodies (DLB), among other less common disor- both neuronal and non-neuronal cells in the brain. Most ders [4]. The central role of α-syn in LBD originated idiopathic synucleinopathies are age-associated and, from almost simultaneous findings of mutations in therefore, their prevalence is increasing in parallel with thegeneencodingforα-syn (SNCA)infamilialforms the world wide increase in life expectancy [1]. Synuclei- of PD [5], and of α-syn comprising the major protein nopathies are second to Alzheimer’s disease (AD) component of Lewy bodies [3]. amongst the most common neurodegenerative disorders Multiple system atrophy (MSA) is neuropathologically known to cause dementia [2]. As with most neurodegen- characterised by accumulation of aggregated α-syn in ol- erative disorders, there are still no disease-modifying igodendrocytes, inclusions known as glial cytoplasmic drugs, limiting treatment options to symptomatic relief inclusions (GCIs) [4, 6], while LB pathology is absent and palliative measures. Therefore, synucleinopathies and, therefore, MSA is not an LBD. pose a growing socio-economic burden to modern soci- The initial clinical and neuropathological studies eties, and demand urgent attention. which established the distinct clinical and neuropatho- Most synucleinopathies are Lewy body diseases (LBD), logical phenotype of the disorder now known as DLB, as they are characterised by the accumulation of aggre- preceded immunohistochemical methods to detect α-syn gated a α-syn into Lewy bodies (LBs) within vulnerable in human brain tissue, but later revisions of international consensus for diagnostic guidelines now recommend the use of immunohistochemistry [7–11]. * Correspondence: [email protected]; [email protected] Clinical under-diagnosis of DLB [12], and over-diagnosis 1Institute of Neuroscience, The Medical School, Newcastle University, of PD [13, 14], have led to most studies of LBD focusing on Framlington Place, Newcastle Upon Tyne NE2 4HH, UK PD and PDD, leaving DLB historically under-researched Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Outeiro et al. Molecular Neurodegeneration (2019) 14:5 Page 2 of 18 relative to its population prevalence. Increasing recognition clinical diagnosis rates (2.4% - 5.9%) between individual of DLB as a distinct and prevalent age-associated neurode- clinicians working in geographically proximal services generative dementia has stimulated increasing numbers of suggesting that performance could be improved sim- high-quality studies on its aetiology and pathogenesis. Here, ply by better application of clinical methods and by we summarise contemporary findings from this rap- increased use of biomarkers (see section "Biomarkers idly expanding field, focusing on genetics, diagnostic in LBD"). biomarkers and molecular mechanisms. The current clinical diagnostic criteria for DLB are shown in Table 1. Dementia, defined as a progressive The clinical definition of DLB cognitive decline of sufficient magnitude to interfere DLB is now the preferred term [8, 10, 11] for a variety of with normal social or occupational functions, or with previously used clinical diagnoses including diffuse LB usual daily activities, is an essential requirement. Dispro- disease (DLBD) [15–17], LB dementia [18], dementia as- portionate attentional, executive function and visual pro- sociated with cortical Lewy bodies (DCLB) [19], the LB cessing deficits relative to memory and naming are variant of Alzheimer’s disease (LBVAD) [20, 21], and se- typical features. Diagnostic toolkits have been published nile dementia of LB type (SDLT) [22]. to assist clinicians to identify the core clinical features Recognition and definition of the DLB syndrome ori- [29–31] but no DLB-specific cognitive batteries have yet ginally occurred through post-mortem neuropathological been developed. observations, of a particular distribution of LB and LN The item generally causing the most difficulty in as- in the brains of elderly subjects with dementia, followed sessment is the identification of cognitive fluctuation. It by a retrospective review of their clinical histories [23]. is recommended to use one of several published This revealed two major findings – the first was that a methods which typically use a series of structured ques- significant number of LB pathology cases had a clinical tions asking: (i) about changes in the patient’s level of presentation that was discernibly different from other functioning during the day; (ii) about excessive daytime dementia subtypes, even at an early stage in the disease. drowsiness; or (iii) about difficulty in arousing the pa- Fluctuating levels of cognitive impairment, recurrent vis- tient so they maintain attention throughout the day. ual hallucinations, spontaneous extrapyramidal motor RBD can be difficult to differentiate from the numerous features and a history of rapid eye movement (REM) other sleep disturbances that can occur in dementia un- sleep behavior disorder (RBD) were the most prominent less the care-taker is specifically asked whether they have symptoms, and the presence of two or more of these ever seen the patient appear to "act out his/her dreams" symptoms in an individual with dementia is now consid- while sleeping (punching or flailing arms in the air, ered sufficient for a clinical diagnosis of probable DLB. shouting or screaming). Assessment of parkinsonism can The other major observation was that approximately be problematic, especially when the clinician is not an 50% of subjects showing full blown DLB pathology at expert movement disorder neurologist, since motor fea- neuropathological post-mortem examination did not tures may be absent in up to 25% of autopsy confirmed show the characteristic clinical picture of DLB during DLB cases and, even when present, may be very mild. life but typically presented with global cognitive decline Documentation of only one of the cardinal features, reminiscent of AD. Unsurprisingly, such cases usually bradykinesia, resting tremor, or rigidity, is required for show additional high levels of AD neuropathological DLB, while at least two are required to diagnose PD. change [24, 25]. The true prevalence of such mixed Co-morbidities, e.g. arthritis, or inability to comply with pathology cases is unknown but autopsy studies indicate neurological examination because of cognitive impair- that between a third and a half of carefully clinically di- ment may lead to false positive diagnoses. agnosed AD show at least some degree of LB pathology Recurrent, complex visual hallucinations, which occur at autopsy [20, 26]. Complex visual hallucinations are in the majority of DLB patients, pose less problems of the only clinical feature indicating the likely presence of recognition, provided that the clinician asks directly LB pathology in an otherwise typical AD case [27], but about them and quantifies their severity with an appro- robust data on progression, prognosis and response to priate scale. They are typically well formed, featuring treatments of “mixed AD+DLB” (i.e.,
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