Title: A review of the perceptual and attentional-executive characteristics of dementia with Lewy bodies relative to Alzheimer’s and Parkinson’s disease
Authors: Lauren Revie 1, Anthony Bayer 2, Christoph Teufel1, Claudia Metzler-Baddeley1
Affiliation: 1Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Maindy Road, Cardiff, CF24 4HQ 2University Hospital Llandough, Penlan Road, Penarth, Cardiff, CF64 2XX
Corresponding author: Lauren Revie Cardiff University Brain Research Imaging Centre (CUBRIC) Maindy Road Cardiff Wales United Kingdom CF24 4HQ [email protected]
Declaration of interest: The authors have no declaration of interest to declare.
Funding: This work was funded by the School of Psychology Open Competition Studentship, Cardiff University, awarded to LR as part of a doctoral programme of study.
1 Abstract
Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia disorder, after Alzheimer’s disease (AD). DLB is characterised clinically by cognitive fluctuations, visual hallucinations, rapid-eye-movement sleep behaviour disorder, and Parkinsonism.
Differentiating DLB from AD and related disorders of Parkinson’s disease (PD) and Parkinson’s disease with dementia (PDD) can be difficult at early disease stages due to overlapping clinical and pathological features. Nevertheless, it has been shown that visuoperceptual, attention and executive deficits, relative to memory impairments, are especially prominent in the early stages of DLB compared with AD or PD. The importance of these impairments is reflected in the recent revision of the diagnostic consensus guidelines of DLB. As the last reviews of cognitive impairments in DLB were conducted over a decade ago (Collerton, Burn, McKeith & O’Brien, 2003; Metzler-Baddeley,
2007; Ralph, 2001), we provide an up-to-date review of the literature into perceptual and attention- executive functions in DLB. There is a need for better controlled studies into cognitive deficits, their neural correlates, and relationships to clinical symptoms in DLB, that go beyond standard clinical assessments. Evidence regarding visuoperception suggests that low-level functions may be relatively preserved while mid- and higher-level functions, that require the recruitment of attention and executive functions are disproportionally affected in DLB. Cognitive fluctuations and visual hallucinations may arise from a desynchronization of top-down attention and bottom-up sensory networks.
Keywords: dementia with Lewy bodies, perception, attention, executive, memory, Lewy body disease,
Alzheimer’s disease, Parkinson’s disease
2 INTRODUCTION
Dementia with Lewy bodies (DLB) is the second most prevalent form of neurodegenerative dementia after Alzheimer’s disease (AD). Its mean prevalence in clinical (secondary care) dementia populations is 7.5% (Vann Jones & O’Brien, 2014). In the most recent consensus criteria, DLB is characterised by four core clinical features (McKeith et al., 2017). First, cognitive fluctuations which occur in up to
90% of patients and are characterised by variabilities in their level of arousal and cognitive performance. This ranges from episodes of stupor and confusion, to periods of alertness and responsiveness (O’Dowd et al., 2019). Second, complex visual hallucinations, which occur in up to
80% of patients, and typically consist of perception of people, animals and objects, motion, and scenery that are not present (Onofrj et al., 2013). Complex hallucinations in DLB are commonly associated with apathy and anxiety and are typically reported by patients as being unpleasant experiences (Mosimann et al., 2006). The third core symptom in DLB is Parkinsonism, which involves disordered movement such as shuffling gait and rigidity. Finally, the fourth core symptom in
DLB is rapid-eye-movement sleep behaviour disorder (RBD), involving the violent ‘acting’ of dreams, and prominent movement and speech during sleep (Ferman et al., 2011). Features which must also be present for a diagnosis of DLB include: a progressive cognitive decline of sufficient magnitude to impact on daily life, and impairment on tests of visuoperceptual, attentional and executive functioning in early disease stages (McKeith et al., 2017). Moreover, with the progression of the disease, memory impairments also become more prominent.
Patients with DLB have pathological inclusions in neurons in the neocortex, midbrain and limbic system that are called ‘Lewy bodies.’ These inclusions consist of ubiquitinated, misfolded α- synuclein, and are also characteristic features of Parkinson’s disease (PD), and Parkinson’s disease with dementia (PDD). Together, these three disorders form the ‘Lewy body spectrum’ (Kövari,
Horvath, & Bouras, 2009). The location of the deposition of Lewy bodies in the brain is closely
3 associated with the presentation of Lewy body disease symptoms. For instance, PD patients present mainly with brainstem and midbrain Lewy body pathology, which co-occurs with clinical motor symptoms. With the progression of PD, patients may go on to develop significant cognitive impairments resulting in PDD, which is associated with the spread of Lewy body pathology to the neocortex (Braak et al., 2003). In fact, the clinical phenotypes of PDD and DLB are very similar, and the only diagnostic difference at present is the chronology of the onset of motor symptoms within a
12-month period (Jellinger & Korczyn, 2018; McKeith et al., 2017).
Despite consensus guidelines which specify the symptom profile of DLB (McKeith et al., 2017) and availability of assessment toolkits to aid diagnosis (Thomas et al., 2018a), DLB is clinically under- diagnosed, as evidenced by a persisting disparity between in-vivo and post-mortem diagnosis rates (;
Arnaoutoglou, O’Brien, & Underwood, 2019, McKeith et al., 2000). Due to the presentation of cognitive and memory impairments, DLB patients can be misdiagnosed as having Alzheimer’s disease (AD; Hohl, Tiraboschi, Hansen, Thal, & Corey-Bloom, 2000) and DLB and AD pathology often co-occur (Thomas et al., 2018b). Moreover, a differential diagnosis between DLB and PDD due to concurrent presentation with both motor and cognitive symptoms can also be challenging (Hely et al., 2008). These issues have important implications for management. Cholinesterase inhibitor treatment is more effective in DLB than AD (Aarsland, Mosimann, & McKeith, 2004; Noufi, Khoury,
Jeyakumar, & Grossberg, 2019). Furthermore, it is more beneficial in treating DLB symptoms than typical dopaminergic treatment that may be prescribed due to misdiagnosis as PDD, or PD, but will only produce a motor response in about one third of DLB patients (Molloy et al., 2005). Most importantly, DLB patients exhibit severe adverse reactions to antipsychotic medication that may be prescribed for the management of psychiatric symptoms in AD patients. Thus, an accurate early diagnosis is helpful for appropriate disease management and treatment to maintain the patients’ quality of life. In addition, recent research has indicated that individuals who receive a later diagnosis of DLB tend to present with symptoms which may not be initially associated with DLB, such as
4 amnestic presentation, which was linked to lower survival probability (Moylett et al. 2019). In the future, the emergence of disease-modifying drugs will demand the identification of specific pathology so that treatments can be targeted appropriately.
Previous literature reviews have summarised research on the cognitive profile of DLB (Collerton,
Burn, McKeith, & O’Brien, 2003; Metzler-Baddeley, 2007; Ralph, 2001). As described above the most prominent cognitive impairments in DLB, especially at early stages, occur in the visuoperceptual, attention and executive domain. The recent revision of the DLB consensus guidelines for diagnosis has emphasised the importance of a detailed assessment and understanding of the nature of these cognitive deficits to aid differential diagnosis of DLB from AD and PDD
(McKeith et al., 2017). As previous reviews were published over ten years ago (Collerton, Burn,
McKeith, & O’Brien, 2003; Metzler-Baddeley, 2007; Simard, 2000), an up-to-date perspective on the cognitive profile in DLB is therefore timely.
Much of the work concerning DLB in recent years has focused on pathology (Kon, Tomiyama, &
Wakabayashi, 2019), genetics (Orme, Guerreiro, & Bras, 2018), determining prodromal or early stage biomarkers (Cagnin et al., 2013; Donaghy & McKeith, 2014; Fujishiro et al., 2013; Outeiro et al.,
2019), and both pharmacological (Hershey & Coleman-Jackson, 2019) and non-pharmacological interventions (Connors et al., 2018). Some neuroimaging evidence regarding structural and functional differences in DLB also exist, which largely align with the previously established supportive features of DLB, such as a link between visual impairments and occipital hypo-metabolism (Perneczky et al.,
2008). These aspects have been reviewed recently by others (Mak, Su, Williams, & O’Brien, 2014;
Watson, Blamire, & O’Brien, 2009; Yousaf, Dervenoulas, Valkimadi, & Politis, 2019). Papers have been also published by Aarsland, (2016) and Jurek et al., (2018) which provide readers with an up to date and detailed summary of the clinical symptom profile in DLB. In addition, a recent systematic review by Eversfield & Orton (2018) discussed hallucination prevalence in DLB.
5 Methods
This review focused on studies into visuoperceptual, attentional and executive impairments, as these are the most prominent cognitive features in DLB. Neuroimaging studies were included in as much as they were informative of the neural correlates of perceptual and cognitive deficits.
Studies included were identified using electronic database search systems PubMed, PsychNET and
Google Scholar. Studies were published in English from 2007 with the final literature search for the review conducted in May 2019. Key words used for the search were ‘dementia with Lewy bodies’ or
‘Lewy body dementia’ in combination with the following terms: ‘cognition’, ‘attention’, ‘executive’,
‘perception’, ‘construction’, ‘visual’, ‘vision’, ‘auditory’, ‘olfactory’, ‘hallucination’, ‘cognitive fluctuation’, ‘Alzheimer’s disease’, ‘Parkinson’s disease’, and ‘neuropsychology’. These search terms produced a total of 1,681 articles. From these articles, only those which assessed cognition and/or perception in a group of DLB patients compared with other patient or control groups (AD, PD, PDD,
Corticobasal syndrome, Multiple System Atrophy, Progressive supranuclear palsy, idiopathic RBD, a subgroup of DLB and/or healthy control group) were included. In addition, only studies in which patients were diagnosed in accordance with the diagnostic guidelines for DLB were included in the review (McKeith et al., 2005; McKeith et al., 2017). Studies which did not include cognitive and/or perceptual testing as the primary focus and/or in combination with another measure, such as those observing only epidemiology, genetics, pathology, treatment in isolation or case-studies were not included (total discarded 1,637). For an overview of methodological features of the studies included in this review, see Table 1.
PERCEPTION
6 DLB is associated with perceptual deficits that have most widely been studied in the visual domain.
However, investigation into perceptual impairments in other domains, including olfaction and auditory perception are increasing (see Table 2).
Visual perception in DLB
A number of organisational principles have been suggested to explain information-processing in the human visual system. Three of these principles are of particular interest in the context of perceptual impairments in DLB. First, that the visual system comprises a number of hierarchically organised regions which functions to process elements of a visual object and form the final interpretation of incoming information (Hubel & Wiesel, 1962). Sensory neurons within different areas are ‘tuned to’ different types of features, increasing in size and complexity as information travels along the hierarchy. For instance, in V1 neurons mainly respond to oriented edges, in V2 neurons respond to lines, angles and contour, V3 is largely associated with segregation of foreground from background features, V4 is associated with shape processing, and V5/MT with processing of motion (Allman,
Miezin & McGuinness, 1985). More generally, visual function is often grouped into three categories:
(i) low-level vision, which is mainly concerned with simple features, (ii) mid-level vision that leads to linking of simple features into larger units, and (iii) high-level vision, which is largely focussed on object perception.
A second principle of perceptual processing that is of interest in the context of DLB is the idea of different streams of information processing. For instance, a classic hypothesis argues that the visual system beyond V4 is separated into a ventral stream, mainly linked to object recognition, and a dorsal stream, largely concerned with spatial localisation (Ungerleider & Mishkin, 1982). The dorsal stream is thought to include areas of the posterior parietal cortex, and the ventral stream includes regions in the temporal cortex, and lateral occipital areas (Mishkin, Ungerleider & Macko, 1983). There is, however, large disagreement in the literature as to how separated these streams really are, and what type of information they are dedicated to.
7 Finally, a third principle of visual information-processing is the idea that perception is a product of the interaction between bottom-up and top-down processing. Bottom-up processing is concerned with basic sensory information that is typically processed automatically and, in some cases, unconsciously.
Top-down processing is a more complex function. Initially considered to be a modulatory process influencing attentional allocation, top-down processing is now thought to interact with bottom-up information in such a way that features are ‘optimised’ using higher level object representations to shape the percept (Teufel, Dakin, & Fletcher, 2018).
As previously detailed, visuoperceptual abilities in DLB are more severely impaired than in AD patients, with impairments presenting earlier, and in conjunction with attentional and executive deficits (Metzler-Baddeley, 2007; Collerton et al., 2003; Lambon-Ralph, 2001; Simard et al., 2000).
Studies which have supported these findings typically use clinical tasks such as pentagon copying, in which DLB patients show significantly greater impairments in comparison to AD patients (Ala, 2001;
Cormack, Aarsland, Ballard, & Tovée, 2004). Landy et al. (2015a) have also reported that DLB patients may struggle with more complex aspects of visual search which requires feature binding, and that this may be the product of impairments in occipito-parietal network function. DLB patients are also seen to perform poorly on the Trail Making Task (TMT) in comparison to AD, which requires participants to draw a line between different numbers or letters presented visually (Breitve et al.,
2018). However, these ‘perceptual’ tasks are cognitively complex, in that they require the functioning of additional cognitive domains in order to complete. For example, the pentagon copying task requires participants to both construct the pentagon visually, and also use executive functions such as planning, and praxis. The visual search task requires selective guidance of attention, and the TMT requires elements of executive control such as suppression and planning. As such, the source of the perceptual impairment on these tasks in DLB is very difficult to determine. Considering the cortical organisation and framework of visual perception as described above, it is difficult to distinguish the specific impairment of the processing stages which may be affected in DLB through performance on these tasks. In addition, investigations have concluded that performance on these complex clinical
8 measures of ‘visual perception’, such as pentagon copying may not be the best predictors of cognitive decline in DLB (Brietve et al., 2018).
Limited studies have addressed this issue, such as Metzler-Baddeley et al (2010) who suggested that
DLB patients’ performance was associated with impaired extrastriatal and ventral visual processing.
They assessed performance related to primary visual cortex (V1), extrastriatal, and ventral stream functioning using tasks designed to assess different levels of visuoperceptual processing, from acuity and contrast, to orientation, contour integration, and object rotation in increasing complexity. Findings suggested that DLB patients have a preservation of performance in lower level visual functions, with impairments arising at mid- to high- level processing stages. These results suggest that deficits in visuoperceptual performance in DLB patients are more complex and detailed than previous tasks have demonstrated. More recent research has recruited tasks which assess different stages in visuoperceptual functioning, which can be categorised into low-, mid- and high- levels, as defined above.
Low-level visuoperceptual impairments in DLB
Low-level visual function includes the processing of simple features, such as spatial frequency, contrast and orientation (see Figure 1). Processing of these features has been reported to be preserved in DLB patients, in comparison to patients with Posterior Cortical Atrophy (PCA) and healthy controls (Metzler-Baddeley et al., 2010). Robertson et al., (2016) also reported unimpaired performance on the Benton Judgement of Line Orientation task in DLB patients in comparison to AD and Vascular dementia patients (VaD). Moreover, Oishi and colleagues (2018) found that DLB patients were not impaired in tasks of stereopsis – a lower level function requiring binocular vision for effective depth perception. Taylor et al., (2011) also observed that early visual areas appear to be functionally intact in DLB patients, as assessed by visual cortical excitability measured by transcranial magnetic stimulation (TMS). This was further demonstrated with preserved cortical
9 activity in the early visual system using functional magnetic resonance imaging (fMRI) (Taylor et al.,
2012). One investigation has also reported unimpaired performance on orientation discrimination tasks in RBD patients, who may be at greater risk of developing PD or potentially DLB (Chahine et al., 2016). However, Donaghy et al., (2018) reported significant impairments in a match-to-sample angle discrimination task in patients with Mild Cognitive Impairment (MCI) thought to precede DLB compared with patients with amnestic MCI who were likely to develop AD. Furthermore, another study reported a trend towards poorer angle discrimination performance in DLB patients in comparison to AD patients (Wood et al., 2013). In summary, the evidence regarding low-level visual perceptual processing in DLB is mixed and it remains to be determined which clinical factors including disease stage, task design and comorbidities contribute to low-level vision deficits in DLB.
Mid-level visuoperceptual impairments in DLB
Mid-level vision is studied to a lesser degree and is more challenging to define. There is some controversy around what constitutes mid-level vision, and whether it is useful to determine (Peirce,
2015). Intermediate or mid-level vision may include the processing taking place in visual regions outside of primary visual cortex, but prior to the split into dorsal and ventral streams. According to this definition mid-level vision would include processing in V2 for lines and contour, V3 and V4 for form and colour, and V5 for motion (Li, VanRullen, Koch, & Perona, 2002) (see Figure 1).
Mid-level processes such as colour perception have been reported to be impaired in DLB patients in comparison to AD and control participants, in a colour matching task during fMRI (Wood et al.,
2013). Moreover, DLB patients experience greater colour vision impairment, as measured by a hue identification test, in comparison to AD patients (Flanigan, Khosravi, Leverenz, & Tousi, 2018). In a task requiring participants to arrange a spectrum of colour tiles matched to an example colour, DLB patients experience significantly more impairment in red-green hue matching. Moreover, colour
10 vision impairment appeared in 78% of DLB patients, in comparison to 15% of AD patients. Matar et al. (2019) also reported that patients with DLB experience significant difficulties in colour discrimination, which is related to the incidence of visual hallucinations and visuospatial function (as measured by the clock drawing task). These findings suggest that colour discrimination may be related to the occurrence of visual hallucinations.
DLB patients also show impairments on tasks requiring the detection of contours in shapes and letters in comparison to AD patients, which is an impairment that has high diagnostic specificity (Ota et al.,
2015). DLB patients demonstrate impairments in perceiving contours of abstract shapes and have a poorer perceptual threshold for contour integration (Metzler-Baddeley et al., 2010). In similar tasks in the Hooper Visual Organisation Test which require contour detection in fragmented stimuli, DLB patients have also shown disproportionate impairments in comparison to AD patients (Mitolo et al.,
2016).
DLB patients have significant impairments in processing visual motion tasks, a deficit that remained constant over a 12-month period (Wood et al., 2013). This is consistent with findings of reduced functional activation in the V5 motion area in response to simple motion stimuli in DLB patients
(Taylor et al., 2012). Furthermore, the same study identified reduced perfusion in the occipito-parietal and occipito-temporal regions and the precuneus during arterial spin labelling in the DLB group. In comparison to AD and PD patients, DLB and PDD patients also show significantly impaired performance on tasks of dot motion discrimination (Landy, Salmon, Galasko, et al., 2015b) and of visual texture recognition that required the recognition of images of materials, such as wood and metal (Oishi et al., 2018). In summary, available evidence suggests that DLB is associated with impairments in mid-level visual processing.
High-level visuoperceptual impairments
11 High level vision concerns the representation of objects, faces and scenes, within the dorsal and ventral processing streams. Integration of information within these streams requires effective top- down processing, or influence of prior knowledge on sensory information to form a coherent percept.
DLB patients show poorer processing efficiency of stimuli when completing the Rorschach test – a test in which participants are presented with inkblots and asked to describe what they can see (Kimoto et al., 2017). The Rorschach performance is measured by a derived score called the ‘perception and thinking index’ (PTI), which reflects cognitive and perceptual distortion. DLB patients show lower
PTI scores, in addition to reporting more unusual details in the stimuli than AD patients, suggesting that higher level integration processes may be impaired.
A number of researchers have postulated that impairments in top-down processing may result in visual hallucinations, which is summarised in the perception-attention deficit model of visual hallucinations in DLB (Collerton et al., 2005). This model states that hallucinations occur as a product of over-activated top-down influence which compensates for poor sensory processing in patients.
Furthermore, it has been proposed that DLB patients who experience hallucinations may also adopt a more ‘liberal’ threshold for detection of bottom-up sensory information, as these patients appear to have deficits in separating visual signals from noise – or meaningful information from non- meaningful information - when presented with a prime image (Bowman, Bruce, Colbourn, &
Collerton, 2017). This can be supported by studies in which DLB patients perceived a greater number of meaningful stimuli in ambiguous visual scenes in comparison to AD and controls, suggesting a potential over-activation of top-down influences on visual perception (Yokoi et al., 2014, Uchiyama et al., 2012).
More recently, it has been considered that visual hallucinations may arise when prior beliefs or knowledge - which typically aid in the processing of sensory information - exert undue influence on perceptual processing (Corlett et al., 2018). This has been investigated in psychotic hallucinations, by
12 presenting patients with two-tone, ambiguous stimuli which alone are seemingly meaningless, but when presented with the corresponding photograph (or ‘prior knowledge’) can be easily identified
(Teufel et al., 2015). Patients with hallucinations were shown to favour prior knowledge, over sensory information. This has also been demonstrated in Lewy body patients, and it was also reported that an increased effect of prior knowledge in stimuli processing was related to severity of visual hallucinations (Zarkali et al., 2019).
Visual hallucinations are also present in idiopathic RBD patients, who report seeing figures, objects or faces when they are not present in stimuli (Sasai-Sakuma, Nishio, Yokoi, Mori, & Inoue, 2017). As there is a high conversion rate of idiopathic RBD to DLB, this may suggest that a perceptual impairment in integrating and organizing information is already present in very early DLB and may be related to REM sleep dysfunction. Performance when viewing ambiguous stimuli is also influenced by a primed mood manipulation, with DLB patients reporting significantly more objects that were not presented, in comparison to controls and AD patients (Watanabe et al., 2018). This suggests that the impairment may be an abnormal perceptual bias, modulated by mood, as opposed to lower-level sensory deterioration.
DLB patients also have impaired visual object recognition memory, which is related to greater atrophy in temporal ventral visual stream regions. They have been found to show impaired object comparisons (Metzler-Baddeley et al. 2010) and to perform worse in the Rey Osterrieth copying task
– a figure-background segregation task requiring the participant to copy a complex diagram – relative to AD and VaD patients (Robertson et al., 2016). This performance was also related to lower occipital-parietal perfusion. However, it remains unclear whether object recognition and complex figure memory impairments are a product of lower level perceptual deficits, attentional deficits or both (Mondon et al., 2007). Elder et al., (2016) employed transcranial direction current stimulation
(tDCS) to assess visual and attentional function in DLB. They reported that tDCS intervention applied to the right parietal and occipital cortex resulted in no improvement in visuoperceptual or attentional
13 function in DLB, as measured by a visual task battery, and choice reaction time task. In contrast, dorsolateral prefrontal cortex tDCS resulted in improvements in choice reaction times, but not in visual performance, suggesting that impaired executive functioning could be compensated by tDCS but impaired visual performance could not. However, these findings may be due to a high degree of atrophy already present in the occipital lobe at or the disease stage of the participating patients.
Furthermore, spatial perception – functions related to the dorsal processing stream – are also disproportionately impaired in DLB. DLB patients perform poorly in the spatial subtasks of the
Visual Object and Space Perception (VOSP) battery (Pal et al., 2016) and poor performance in this task was found to correlate with reduced functional connectivity between left and right components of the fronto-parietal executive networks compared to healthy controls (Chabran et al., 2018). This evidence suggests that impairments in attentional processes may not only contribute to visual and memory impairments but may also reflect a surrogate marker of disease severity in DLB.
Olfactory perception in DLB
Olfactory impairment is a supportive clinical feature in DLB and is also characteristic of other Lewy body disorders. Olfactory Lewy body pathology is often present in DLB cases at post mortem examination (Beach et al., 2008), and more recently, ‘olfactory bulb only’ subtype of Lewy body pathological presentation has been included in clinical guidelines (McKeith et al., 2017).
Studies have demonstrated deficits in DLB patients’ odour identification (Westervelt, Stern, &
Tremont, 2003) and odour memory (Gilbert, Barr, & Murphy, 2004). Yoo et al., (2018) demonstrated in autopsy confirmed cases, that patients with Lewy bodies experienced more olfactory dysfunction.
Olfactory dysfunction was also correlated with the presence of white matter abnormalities, as suggested by lower fractional anisotropy and higher mean diffusivity from diffusion tensor imaging
(DTI) in the orbitofrontal and frontoparietal cortices in DLB and PDD patients. Olfactory dysfunction
14 can also distinguish DLB from AD in early disease stages by using a brief smell test in combination with a verbal learning task (Westervelt, Bruce, & Faust, 2016), with DLB patients performing much worse on the olfactory test but much better on the verbal learning test in comparison to AD patients.
Olfactory impairment may also be present in prodromal DLB, or prior to conversion to PDD.
Impairment on a smell identification test in PD patients was found to be related to symptoms of cognitive decline, as opposed to motor symptoms (Westervelt, 2016). More specifically, the severity of olfactory impairment was associated with a decline in executive function and attention over three years, as measured by performance on tests of verbal learning, semantic fluency and letter-number sequencing. Mahlknecht et al., (2015) also reported that olfactory impairment in idiopathic RBD patients were associated with a 7-fold risk of conversion to DLB within 5 years, demonstrating the predictive importance of olfactory perceptual impairment. Interestingly, RBD patients who went on to develop DLB showed both worse baseline olfactory performance and impaired colour vision
(Postuma, Gagnon, Rompré, & Montplaisir, 2010). However, Iranzo et al., (2014) reported no association between smell identification and detection in idiopathic RBD and healthy patients over 4 years.
Perceptual impairments in other modalities in DLB
Impairments in other perceptual modalities have also been reported in DLB patients but the number of studies is very limited. Suárez-González et al., (2014) reported that auditory hallucinations were much more frequent in DLB patients than in AD patients and were typically preceded by a visual hallucination. DLB patients also show a deficit in automatic auditory change detection (Brønnick,
Nordby, Larsen, & Aarsland, 2010), indicating that patients experience difficulty in selectively attending and responding to unexpected auditory stimuli.
15 Summary of perceptual impairments in DLB
Many studies investigating perceptual deficits in DLB focus on visual functioning, which is markedly impaired in DLB patients, in comparison to AD and PD. More recent studies have focused on specific stages of visual processing, and generally report that vision in DLB patients is characterized by relatively intact low-level function and impaired mid to high-level visual processing. However, there is some mixed evidence, as a number of studies report differing results in one specific low-level task, namely, DLB patient’s performance on measures of ‘orientation discrimination’ performance. DLB patients also appear to experience impairments in processing of both ventral and dorsal streams, which has been linked to the incidence of hallucinations. Some studies have demonstrated that these impairments may be the product of reduced functional connectivity and desynchronization in these neural networks. In addition, those more complex tasks that require increased recruitment of attention and executive control were markedly impaired in DLB patients.
The number of studies investigating non-visual perceptual processing in DLB is small. The few studies focussing on olfactory perception show that DLB patients have impaired smell recognition.
However, the evidence as to how predictive these impairments are of DLB severity or progression is mixed. Finally, there is some evidence to suggest that hearing is impaired in DLB patients, but the number of studies supporting this notion is very limited and more research is required to confirm these findings.
ATTENTION AND EXECUTIVE FUNCTIONS
Attention is a complex and multifaceted phenomenon involving multiple cognitive processes, with the ultimate goal of focusing limited resources on behaviourally relevant stimuli (Lezak et al., 2004).
Executive functions recruit a number of cognitive processes, and may be categorised into three core domains: inhibition, working memory and cognitive flexibility (Diamond, 2013). Attention and
16 executive processes are closely interlinked, as executive functions contribute to the ‘top-down’ voluntary aspect of attention and interact with other ongoing cognitive processing to direct appropriate behaviour. Executive functions are largely referred to as ‘frontal’ processes as they are mediated by anterior brain areas including the prefrontal cortex and anterior cingulate cortex and can be disrupted by damage to these brain regions (Zelazo & Cunningham, 2007). Executive processes can contribute to the alternating of attention, selective attention, divided attention, and inhibition, as well as effective visual processing. Attentional processes are often measured by tasks of focal, covert and sustained attention, in addition to specific tasks, such as object-oriented attention, and are necessary for almost all neuropsychological testing. It is challenging to differentiate attentional and executive control when assessing task performance.
One framework of attention suggests that bottom-up, stimulus-driven processes such as alerting, and top-down goal-directed selection work together towards effective attentional processing (Corbetta &
Shulman, 2002). This model is closely related to the dual-stream model of visual processing
(Mishkin, Ungerleider & Macko, 1983), in both functionality and anatomy, and proposes that bottom- up processing is carried out by the ventral attention network, and top-down processing involves the dorsal attention network. The ventral attention network, located in the temporoparietal and inferior frontal cortices, and involving the function of the anterior cingulate cortex (ACC) and the right insula
(Eckert et al., 2009), is specialised for detection of relevant stimuli, and directs attention to salient events. The dorsal attention network, involving the intraparietal and superior frontal cortices is responsible for goal-directed allocation of resources. Both pathways work in collaboration in order to respond to the environment accordingly, which also requires executive functioning, including prioritising and judgement of goal or context-appropriate stimuli (Robbins, 1996).
Another influential model of attention, proposed by Posner & Petersen (1990) posits that attention involves three serial networks: alerting, orienting and executive networks. The alerting network, responsible for the modulation of arousal and maintenance of optimal vigilance, is thought to be
17 located in the right parietal and frontal cortices. The orienting network, which prioritizes incoming information by identifying relevant spatial locations, involves the superior colliculus, frontal, posterior parietal and thalamic regions. The executive network enables target detection, focus and consciousness, and is proposed to involve regions in the anterior cingulate cortex and prefrontal cortex. For a summary of tasks used to measure attention and executive impairments in DLB, see
Table 3.
Attentional and executive impairments in DLB
DLB patients show attention and executive dysfunction, particularly in tasks requiring sustained attention, re-engagement of attention, and inhibition of information, such as the Stroop task, Eriksson
Flanker task and the Wisconsin Card Sorting tasks (WCST; Calderon et al., 2001; Collerton et al.,
2003; Johns et al., 2009; Peters et al., 2012). DLB patients also show greater grey matter atrophy in the ACC and prefrontal cortex, with has been found to correlate with poorer sustained and selective attention, in comparison to PDD patients (Sanchez‐ Castaneda et al., 2009).
Attention and executive impairments may occur up to 6 years prior to a DLB diagnosis (Marchand et al., 2017). Impaired performance in executive and attentional functioning tasks, such as the trail making task (TMT), was the best predictor of RBD to DLB conversion and DLB patients at very early stages show marked impairments in executive tasks including the TMT and Stroop task compared to healthy controls (Petrova et al., 2016).
DLB patients demonstrated poorer performance on tests of executive function in the earliest stages of the disease, in comparison to PD patients (Yoo et al., 2018). Performance on a digit span task also revealed that DLB patients have more severe impairments than AD and PDD (Park et al., 2011).
However, with the development of PD into PDD, patients begin to develop more severe attentional and executive impairments. For instance, Aldridge et al., (2018) found comparable impairments in
18 executive functioning on tasks of digit span and TMT in DLB and PDD patients. The gradual worsening of attentional and executive functioning with progression to PDD may be consistent with the pathological spread of Lewy bodies from the brain stem to the neocortex with the advancement of the disease. DLB relative to AD patients at early disease stages also show greater impairment on tasks requiring effective visual attention – such as the TMT and digit cancellation task - which was also related to poorer performance on the pentagon copying test (Cagnin et al., 2015). These findings suggest that DLB patients are more severely impaired in tasks requiring both visual and executive elements even at early stages of the disease. Moreover, in DLB patients, poorer executive function performance is related to faster progression and reduced longevity in comparison to AD (Brietve et al., 2018). Kao et al., (2009) reported significant performance deficits on TMT and a task of design fluency in DLB patients, compared to other synucleinopathies, PD, and multiple systems atrophy
(MSA). These findings suggest that DLB-related impairments in these tasks may be partly the result of dysfunctional planning abilities.
Neural correlates for attentional and executive impairments in DLB patients, have been revealed in studies using the Attention Network Task (ANT; Fan et al., 2002), which was designed to assess the functioning of the alerting, orienting and executive attentional networks (Posner & Petersen, 1990).
DLB patients show a reduction in sustained alertness and failed to exhibit orienting or executive network mediated congruency effects without an alerting cue, in comparison to AD and control participants (Fuentes et al., 2010). This suggests that, without external cueing or alerting, patients experience difficulties in allocating attentional resources to stimuli. DLB patients also make more errors and have longer reaction times on the ANT during fMRI, in comparison to controls and AD patients (Kobeleva et al., 2017). These findings were related to reductions in functional connectivity between the dorsal and ventral attention networks, and between these networks and frontal regions in
DLB. In addition, DLB patients showed delayed latencies of the blood-oxygen-level-dependant
(BOLD) signal in more challenging ANT trials, which may also reflect disconnection or desynchronization between attentional networks. Overall, the evidence suggests that DLB patients
19 may experience disconnection between anterior and posterior attention networks, resulting in a failure to engage the ‘bottom-up’ ventral attentional network, and leading to an over compensation in the
‘top-down’ dorsal network. Of interest here is also that DLB patients show reductions in white matter volume in the lateral occipital cortex, which were correlated with an impairment in orienting network activation (Cromarty et al., 2018). This white matter disruption might reflect the structural correlates of the observed functional disconnections. Together these findings suggest that impaired orienting may be partly due to impairments in visual network functioning.
Poor ANT performance is also associated with task-related deactivation in the default mode network
(DMN; Firbank et al., 2016). The DMN is a neural network which is thought to be involved in numerous cognitive processes, including wakeful rest and mind wandering. DMN deactivation is thought to be required for the preparation of task-related response (Raichle, 2015). DLB patients were shown to have very strong deactivation of the DMN, which may reflect compensatory processes to inefficiencies in synchronisation between attentional networks (Firbank et al., 2016). The profound deactivation in the DMN was related to slowing of cognitive processing and reaction time in the ANT in DLB patients (Firbank, O’Brien, & Taylor, 2018). Furthermore, abnormal DMN activity in DLB patients appears to go hand in hand with fronto-parietal desynchronization, which in turn was associated with the severity of cognitive fluctuations.
Importantly, there is also a relationship between attentional- executive impairments and clinical symptoms in DLB. Longer reaction times in attentional and vigilance tasks, such as choice reaction time, were related to clinical symptoms and neural correlates of cognitive fluctuations in DLB but not
AD (Taylor, Colloby, McKeith, & O’Brien, 2013). Moreover, these attentional impairments were related to cognitive motor perfusion pattern on single proton emission computerised tomography
(SPECT) scans in the same study. This pattern was associated with increases in perfusion in the cerebellum, basal ganglia and supplementary motor areas and widespread bilateral decreases in the parietal region. Impairments on attentional vigilance tasks are also present in DLB, and were related
20 to the presence and severity of cognitive fluctuations, and bilateral atrophy of the pulvinar, and ventral lateral and dorsal thalamus (Watson et al., 2017). Furthermore, attention and executive impairments have been linked to the incidence of visual hallucinations in DLB. Notably, impairments on tasks such as the Stroop task, digit span and verbal fluency were related to the incidence of psychotic
(hallucinatory) symptoms (Van Assche et al., 2018). Performance in digit cancellation tasks (Cagnin et al., 2013) and in rapid serial visual presentation paradigm (RSVP) (Peters et al., 2012) were related to the incidence of visual hallucinations in DLB.
Executive functions, in particular the allocation of attentional resources, appear to be disproportionately impaired in DLB relative to AD patients. Bronnick et al., (2016) found that impaired executive function performance in the TMT and Stroop task significantly correlated with the incidence of Parkinsonism in DLB. The authors attributed these deficits to the potential dysfunction of the fronto-striatal circuits, resulting in impaired attention, executive and motor abilities.
Working memory impairments in DLB
Working memory refers to the ability to temporarily store and manipulate information for further processing (Baddeley, 2000; Baddeley & Hitch, 1974). The working memory model proposes that attention functions are overseen by an overall controller, organiser and allocator of resources known as the ‘central executive’. The central executive is responsible for controlling attentional focus, selection of strategies and integration of information from other sources, i.e. many of the executive functions discussed above. The central executive is aided by two sub systems: the visuospatial sketchpad, which manipulates visual information, and the phonological loop, which is necessary for speech-based processing. The capacity of the slave systems is typically measured by recalling sequences of digits or locations, whilst executive processing may be taxed with executive functions tasks that require the maintenance and updating of a stream of stimuli such as the n-back task. A further development of the model also introduces the episodic buffer, a structure which provides
21 temporary storage and is responsible for information binding and integration from a number of sources (Baddeley, 2000). The episodic buffer is thought to play a role in processing and retrieval of information from episodic long-term memory.
Whilst episodic memory problems are less pronounced in DLB than in AD, the opposite pattern has been observed for working memory functions, especially when they require central executive control.
DLB patients typically perform better in delayed recall tasks than AD patients, but show greater impairments in executive tasks that require not only the maintenance but also the manipulation of information in short-term memory (Kawai et al., 2013).
Working memory capacity may be reduced in DLB. Impairments in working memory capacity were present in the assessment of prodromal DLB patients using the forward and backward digit span task, in comparison to healthy control participants (Kemp et al., 2017). Some evidence also suggests that working memory capacity impairments in DLB were linked to sleep disruption due to RBD, notably reduced slow wave sleep. Increased periods of short-wave sleep were shown to result in improved working memory performance in PD but not in DLB. The authors conclude that working memory capacity may be modifiable in PD, following medication or correction for sleep disturbances, however sleep does not improve working memory capacity in DLB patients (Scullin, Trotti, Wilson, Greer, &
Bliwise, 2012).
Conversely, evidence has also suggested that attentional binding, i.e. the ability to integrate features within complex stimuli or events between short and long-term memory appears to be preserved in
DLB (Della Sala, Parra, Fabi, Luzzi, & Abrahams, 2012). Attentional binding tasks require participants to immediately recall visual stimuli characterised by either a single feature (such as colour) or features, which required binding in memory (such as coloured objects). DLB patients showed no impairment in short term memory binding in comparison to healthy control participants, patients with frontotemporal dementia (FTD), Vascular dementia (VaD) and AD (Della Sala, Parra,
22 Fabi, Luzzi, & Abrahams, 2012). These findings contrast with the results from the contour integration tasks (Metzler-Baddeley et al 2010), in which DLB patients had difficulties in binding visual information. These contrasting findings may suggest that DLB patients are able to bind once attention is sufficiently allocated, however when more attentionally demanding visual stimuli are present, integration of different visual information may be disrupted. More specifically, DLB patients may able to bind information of two distinct features, such as object and colour, when presented independently, but are unable to recognize and bind objects in within surrounding stimuli, otherwise known as ‘crowding’ (Ehlers, 1936).
Summary
It is evident that there are marked impairments in attention and executive functions in DLB, in comparison to AD and PD, which are present from very early disease stages (Ciafone et al., 2019).
Moreover, impaired executive functioning is related to faster disease progression in DLB. More recent investigations have suggested that attentional networks responsible for alerting may result in impaired attentional processes, and that a potential disconnection and desynchronization between attentional networks may underpin DLB patients’ attention deficits. In addition, attentional vigilance performance has been linked to the incidence of cognitive fluctuations, and digit cancellation task performance is related to the incidence of visual hallucinations in DLB. Finally, there is some evidence to suggest that working memory capacity is intact in DLB patients, however evidence investigating the manipulation of information in working memory and binding remains unclear.
DISCUSSION
Previous reviews have summarised the cognitive impairments in DLB, concluding that DLB patients experience marked deficits in visual processing and attention. More recent studies revealed that these deficits may be more specific and may affect selected aspects of perceptual and attentional processing in DLB. In particular, DLB patients may not experience global visual deficits but might be
23 characterized by specific impairment in mid to high level vision, with low-level visual function being relatively spared at earlier stages of the disease.
The nature of visual impairments, and relationship to attentional and executive dysfunction in DLB
Some inconsistencies in the literature are present, with some studies reporting preserved function only in the most basic aspects of vision such as visual acuity and contrast sensitivity with impairments in orientation and angle discrimination up to higher level visual processing stages (Donaghy et al., 2018;
Wood et al., 2013), whilst other studies found preserved orientation abilities (Chahine et al., 2016;
Metzler-Baddeley et al., 2010, Robertson et al., 2016). In particular, those studies which used an angle discrimination task as a measure of orientation ability have reported impairments in DLB patients
(Donaghy et al., 2018; Wood et al., 2013), whereas those studies which have recruited orientation discrimination tasks such as the Benton judgement of line orientation task tend to report intact orientation function in DLB (Chahine et al., 2016; Metzler-Baddeley et al., 2010, Robertson et al.,
2016). These disparities may be related to the complexity of the task stimuli as angle discrimination is most likely a mid-level process, rather than reflecting low-level vision. There is evidence suggesting that the overall shape of the angle influences angle discrimination, i.e. that processing of global aspects of the stimulus is involved rather than orientation alone (Kennedy, Orbach & Loffler, 2006).
In fact, more recent work has reported that angle discrimination consists of two distinct processes.
First, encoding the orientation of lines in the stimuli, and second, by estimating the angle in an internal reference frame (Xu, Chen & Kuai, 2018). This is of particular relevance in the context of
DLB perceptual impairments, as by this definition, angle discrimination is reliant on prior knowledge of angles in the world. As DLB patients have an over-activation or reliance on prior information during visual processing (Collerton et al., 2005; Corlett et al., 2018), angle discrimination may also be subject to such biases. Thus, further investigations into visual perceptual performance should attempt to disentangle orientation discrimination from global processing abilities to determine the nature of orientation impairments in DLB.
24 As discussed, many previous studies have used standard clinical or neuropsychological tasks, which are useful in the screening of DLB. However, these tasks are not specific enough to identify the exact processes that contribute to the complex nature of cognitive deficits in DLB (Brietve et al., 2018).
Impairments in visual tasks appear to worsen with the increased need to recruit attentional resources or executive functions such as planning. Future studies should incorporate specific visual tasks, which relate to the functioning of primary visual and extrastriatal brain regions, in order to better characterise these impairments in DLB. In addition, limited studies have employed psychophysical methods to obtain more specific and more sensitive performance threshold measures for visual perception, which allow more detailed characterisation of impairments in DLB. It is also of interest in the future to consider not only more specific perceptual deficits in DLB, but also their neural correlates in the brain that may differ from other dementia disorders.
In addition, marked attention and executive dysfunctions and poor processing speed can be observed even at very early stages in DLB, in comparison to AD and PD (Ciafone et al 2019). These executive deficits have been linked to a faster progression of the disease in DLB, compared to AD patients.
Similarly, working memory deficits are present in DLB, in particular during tasks which require executive control of information to be held and processed temporarily. In contrast, working memory capacity and short-term memory binding and integration of information, are relatively preserved
(Della Sala, Parra, Fabi, Luzzi, & Abrahams, 2012; Kemp et al., 2017). These findings contrast with studies which have reported binding deficits in visual information integration (Metzler-Baddeley et al., 2010). Specifically, as DLB patients appear to show unimpaired performance on tasks requiring
STM binding yet show impairment in tasks requiring visual binding of features within larger surrounding stimuli. This suggests that DLB patients may experience crowding, in which target contours are missed, due to the influence of near-by elements. The exact mechanism by which crowding occurs is unclear, and may be related to both top-down attentional impairment, or individual differences in lower-level receptive field (Levi, 2008). Future investigations into binding performance and visuoperceptual and/or executive functioning in DLB should therefore consider the potential influence of crowding in this patient group.
25 Neural networks implicated in visual and attentional impairments in DLB
Some studies have investigated visual network dysfunction in DLB patients, finding that both ventral and dorsal visual processing streams appear to have reduced functional connectivity, in addition to
DMN deactivation impairments during attentional tasks (Firbank et al., 2016). Disconnection between attentional networks responsible for alerting, orienting and executive functions may contribute to their desynchronization and hence slowing of processing speed and deficits in higher order attentional functions (Kobeleva et al., 2017). Most notably, deficits in attentional processing may be related to an impairment in disengagement of the DMN (Firbank et al., 2016). However, the relationship between functional and structural network impairments in DLB remains unclear.
Functional connectivity deficits may reflect impairments in underlying brain microstructure and future research may clarify the precise nature of network dysfunction in DLB (Greicius, Supekar, Menon, &
Dougherty, 2009). For instance, longer reaction times have been shown to be associated with decreased BOLD signal on fMRI as well as reduced fractional anisotropy (FA) in white matter (Baird et al., 2005). Such DLB-related white matter microstructural impairments have been reported in tracts related to visual processing streams, such as the inferior longitudinal fasciculus (Kantarci et al., 2012).
Reductions in FA have also been found in the parieto-occipital regions in DLB patients (Watson et al.,
2009). These findings suggest that white matter impairments may underlie the functional network connectivity impairments reported in the literature – or vice versa - and could result in cognitive impairments present in DLB patients.
Potential mechanisms involved in cognitive and perceptual impairment in DLB
Another possible mechanism for reduced connectivity is disrupted neurochemistry, in particular
Gamma amino-butyric acid (GABA), which plays a key role in visual processing, attention and visual hallucinations (Edden, Muthukumaraswamy, Freeman, & Singh, 2009; Khundakar et al., 2016).
GABA, as detected on magnetic resonance spectroscopy (MRS) is reduced in occipital regions and
26 the temporal lobes in PD patients with complex visual hallucinations (Firbank et al., 2018), in addition to widespread white matter microstructural impairments. These findings suggest that neurochemical and microstructural changes in visual processing regions may result in ventral visual stream disturbances, resulting in hallucinations. Moreover, regional GABA concentrations are shown to modulate intrinsic connectivity in the DMN (Haag et al., 2015). As DMN dysconnectivity was reported in DLB patients, in connection to impaired attentional performance, GABA may play a key role in this cognitive deficit. Higher GABA was also related to increased response inhibition and switching processes, in addition to attentional gating and subsequent speed of response (Quetscher et al., 2015). GABA levels in the anterior cingulate cortex (ACC) – a region responsible for conflict monitoring – were also found to be associated with functional activation and connectivity in the fronto-striatal network. As such, a reduction in functional connectivity and associated cognitive deficits may reflect GABAergic metabolite imbalance or synaptic dysfunction in DLB.
It has also been suggested that inflammation may play a role in the pathophysiology of DLB and may underlie cognitive impairments. Chronic increased inflammatory markers in the brain are linked to cognitive decline in midlife, including executive functioning, attention and episodic memory
(Salthouse, 2004), and higher levels of peripheral inflammation appear to predict future cognitive decline to an extent (Marioni et al., 2009). Moreover, inflammation is related to impaired white matter microstructure (Wersching et al., 2010) and reduced grey matter volume (Satizabal, Zhu, Mazoyer,
Dufouil, & Tzourio, 2012). Increased inflammatory markers such as activated or dysfunctional microglia have been reported in post mortem assessments of DLB brain tissue, and have been linked to neurodegenerative changes in other dementia disorders (Streit & Xue, 2016). The brain’s inflammatory response has been associated with decreased functional connectivity in prefrontal regions using fMRI, which could suggest a potential mechanism by which BOLD signal is reduced in
DLB patients in attentional networks. However, the role of inflammatory processes in the formation or progression of Lewy body pathology remains unknown at present.
27 The relationship between cognitive impairments in DLB patients and underlying neural correlates and changes may be key in the understanding of pathological mechanisms of the disease. Notably, the relationship between GABA and cognitive impairment in DLB may provide an important avenue for investigation and may provide further insight into the unique brain changes present in the disease.
Conclusions and future directions
In conclusion, DLB patients experience problems in mid-level visual perception, with relative preservation of low-level visual functions. In addition, visual performance becomes more challenging with increasing attention demands in DLB. However, in attention-executive based tasks, DLB participants are able to perform if attention can be initially engaged, suggesting that bottom-up deficits may affected higher-order processing in DLB. Further theoretically-driven studies are required to determine the relationship between visual and attention-executive impairments in DLB. In addition, observing the neural correlates and network functioning related to these impairments may aid in the understanding of the aetiology of these unique cognitive deficits, and pathophysiology of the disease. Future challenges will then lie in determining the relationship between pathological, neurobiological, functional, and clinical investigations in order to obtain a broader profile of cognition in DLB patients.
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35 Figure 1. Visuoperceptual organization in the cortex. Schematic diagram depicting the dual stream model of visuoperceptual organization. Following sensory information processing from the retina through the optic nerve to the lateral geniculate nucleus (LGN), information is firstly processed via the optic radiations to primary visual cortex (V1). Information is then processed in a hierarchical manner with increasing complexity of perceptual elements. Finally, information is processed via the dorsal stream (spatial information), or ventral stream (object information) requiring input of frontal executive functions. Overlap of dual stream attentional model is also demonstrated. IP/SPL = intraparietal/ superior parietal lobule, VFC = ventral frontal cortex, FEF = frontal eye fields, TPJ = temporoparietal junction.
36 Table 1. Methodological features of studies reviewed. CSF = corticospinal fluid, MRI = magnetic resonance imaging, SPECT = single photon emission computed tomography, DRS = dementia rating scale, fMRI = functional magnetic resonance imaging, GDS = global deterioration scale, MIBG = metaiodobenzylguanidine, tDCS = transcranial direct current stimulation, TMS = transcranial magnetic stimulation, SVD = small vessel disease, RBD (REM sleep behaviour disorder),, LBD = Lewy body disorder ACE = Addenbrooke’s Cognitive Exam
Author (year) Mean age DLB Mean MMSE Number DLB Other Matching Other measures DLB patients group(s) criteria
Aldridge et al 72.3 - 22 PDD Education, - (2018) handedness,
Andersson et al 76 21 47 PDD, AD Age, MMSE CSF profile (tau, A-β) (2010)
Ash et al (2012) 75.1 22.2 9 PD, healthy - Structural MRI control
Bowman et al 71.06 16 hallucinators Healthy (2017) (Hallucinators) - 19 non- control - - 66.5 hallucinators (Non- Hallucinators) Brievte et al 76 23.3 72 AD Education, age - (2018)
Bronnick et al 77.3 21.1 17 PDD, PD, FP-CIT SPECT (2010) AD, healthy - control
Bronnick et al 76.29 23.63 77 AD Age, MMSE MRI, bloods (2016)
Cagnin et al 74.7 22.7 81 AD Age, sex, - (2012) education
Cagnin et al 76.5 27.8 25 AD Age, sex, - (2015) education
Chabran et al 73 24 26 Healthy Sex fMRI (2018) controls, AD
Chahine et al 61.9 18 (MDS) 108 RBD patients PD patients Age, sex, - (2016) without education, RBD disease duration
Crowell et al 75.2 20.4 21 AD, healthy Age, education - (2007) control
Della Sala et al 72.9 19.8 10 PD, AD, - - (2012) FTD, VaD
Donaghy et al 75.5 26.5 41 MCI-AD Age, edcucation FP-CIT SPECT (2018)
Elder et al 65 20.6 5 PDD Age tDCS (2016)
37 Flanigan et al 78 16 (MOCA) 24 MCI-AD, - - (2018) AD, MCI- DLB
Firbank et al 75 (CAMCOG) 76.7 32 AD, healthy - - (2016) control
Fuentes et al 76 (2010) 22 13 AD, healthy Age, sex, - control education
Hamilton et al 73.4 22.6 22 AD Age, education, Neuropathology (2008) MMSE
Johns et al 73.3 23.83 15 FTD, - - (2009) healthy controls Kao et al 70 27 12 PD, MSA Age, sex, disease - (2010) duration
Kawai et al 79.7 19.1 38 AD - - (2013)
Kimoto et al 80.91 17.42 32 AD, healthy Age MRI, PET (2017) control
Kobleva et al 74.7 23.3 30 AD, healthy Age fMRI (2017) control
Landy et al 75.1 24.1 15 AD, PD, Age, education - (2015b) PDD, healthy control
Landy et al 73.4 23.2 17 PD, healthy - - (2015a) control, PDD, AD
Mahlknecht et al 68.2 - 3 PD, RBD, Age Odour identification (2015) healthy controls Marchand et al 76.7 25.06 18 PD, RBD - Polysomnography (2016)
Matar et al 74.1 23.4 24 Healthy Age, sex - (2019) controls
Metzler- 74 19.4 10 PCA, Age, sex, - Baddeley et al healthy education (2010) control
Mitolo et al 74.18 24.04 28 AD, healthy Age, education - (2016) controls
Mondon et al 78 16 8 PDD Age, education, - (2007) motor score
Oishi et al 82.3 20 25 AD, healthy Age, sex - (2018) controls
Ota et al (2015) 79.1 18.1 35 AD Age, education, MRI, PET MMSE Pal et al (2016) 72 19 3 FTD, AD, - - VaD, healthy control Park et al 70.4 20.2 10 AD, PD - - (2011)
38 Peters et al 85.1 24.2 15 AD, healthy Age, sex (2012) controls
Petrova et al 68.9 25.7 24 Education, - (2015) MMSE
Petrova et al 73 21.1 21 AD, very Age, education - (2016) mild DLB, healthy control
Robertson et al 76 21 (MOCA) 15 SVD Age, sex, Orthostatic (2016) education hypertension, fMRI
Sanchez- 71.1 4.18(GDS) 12 PDD, - MRI Castaneda et al healthy (2009) controls
Sasai-Sakuma 66.8(RBD) 93 (ACE) 202 Healthy Age, sex, Polysomnography et al (2017) controls education
Suarez- 75.9 17.38 80 AD Age, disease - Gonzalez duration, MMSE, (2014) functional impairment Scullin et al 70 21.5 10 PD - - (2012)
Taylor et al 80.6 19.1 21 Healthy Age, sex TMS (2011) controls
Taylor et al 81.2 18.8 17 Healthy Age, sex, visual fMRI (2012) controls acuity
Taylor, 76.2 16.2 19 AD Age, sex, MRI, perfusion Colloby, MMSE, disease McKeith & duration, ChEI O’Brien (2013) use
Van Assche 76.2 24.86 49 AD, late Age, MMSE, - (2018) onset severity disease, psychosis time medicated
Watanabe et al 79.8 16.5 36 12 Age, sex, - (2018) education, visual acuity, MMSE Watson et al 78.4 20.3 35 Healthy - MRI (2017) control
Westervelt et al 77.62 23.08 26 AD Age, education, - (2016) disease duration,
Wood et al 78.4 22 26 AD, Healthy Age, sex, - (2013) control education, disease duration
Yamamoto et al 73.3 - 73 AD Age, disease - (2017) duration
Yoo et al 70.15 24.94 217 AD - MRI, diffusion (2018)
Yoon et al 71.2 25.2 20 PD MMSE, Age, FP-CIT PET, MIBG (2014) education scan
Zarkali et al 68.9 28.5 37 LBD Healthy MMSE, MOCA, Smell test (2019) control Age, education
39 40 Table 2. Results of studies assessing perceptual functions in DLB patients in comparison to other patient groups and controls. Neuropsychological tasks are sectioned by recruitment of perceptual process as stated in individual studies (visual, auditory, olfactory). WAIS = Wechsler Adult Intelligence Scale, CAMCOG = Cambridge Cognition Examination, TMT = trail making test, HC = healthy controls, AD = Alzheimer’s disease, DLB = dementia with Lewy bodies, PD = Parkinson’s disease, PDD = Parkinson’s disease dementia, VaD = Vascular dementia, FTD = frontotemporal dementia, VLOSP = very late onset schizophrenia like psychosis, AD+P = Alzheimer’s disease with psychosis, PCA = posterior cortical atrophy, iRBD = idiopathic REM sleep behaviour disorder, SVD = small vessel disease, RBD = REM sleep disorder patients
Bowman Breitve Bronnick Chahine Donaghy Elder Flanigan Kimot Landy et Mahlknecht Matar et al Metzler- Mitolo et al et al et al et al et al et al et al et al o et al al (2015b) et al (2015) (2019) Baddeley et (2016) (2017) (2018) (2010) (2016) (2018) (2016) (2018) (2017) al (2010)
- DLB ------Visual perception =AD MMSE Pentagon copying
- - - - MCI------ACE-R Visuo-spatial DLB< MCI-AD
------Cube copying
------Clock drawing
------DLB< AD Hooper VOT
- VOSP: Cube analysis - DLB ------=AD
- VOSP: Silhouettes
------
------VOSP: Incomplete letters
------VOSP: Object decision
VOSP: Dot counting ------
VOSP: Position discrimination ------
41 VOSP: Number location ------
VOSP: Incomplete Letter subtest ------
Cog-Pro: Orientation ------DLB= PCA -
Cog-Pro: visuo------DLB> PCA - construction -
------DLB> PCA - Cog-Pro: Perception
-
- - - - MCI-DLB - - - DLB, - - - - Dot motion = MCI-AD PDD< AD, PD
------DLB no - Simple motion improvem ent tDCS
------DLB, - Object rotation PCA ------DLB MOCA - - - RBD DLB< Rorschach ------AD, - - - - - HC Block design test ------ MMSE orientation ------ ------Benton visual retention - - - RBD =PD ------DLB=HC> - Benton Line orientation PCA MCI- DLB - - - - DLB< no ------DLB< AD - - - - MCI------Rey complex figures DLB= MCI-AD 42 ------Overlapping figures Poppelreuter task ------ Raven’s progressive ------matrices Freidberg Visual Acuity ------DLB= HC> - (FRACT) PCA DLB, PDD, PD ------Ambiguous visual images + Hall< (pareidolia) PD + No Hall, HC ------Illusionary contours Material (texture) recognition ------ City University Colour Vision Test (CUCVT) ------ 15 hue Colour test ------ Fransworth-Munsell 100 ------DLB Visual Perpception Test Agnosia ------ Random Dot Stereopsis Butterfly Test ------ Developmental Test of Visual Perception ------(Position in Space) Two-tone Visual Learning ------Paradigm 43 Auditory DLB, PD> Auditory odd-ball - - PDD ------ Mismatch negativity DLB, PD> auditory task - - PDD ------ Olfactory Cross cultural smell ------identification Brief smell identification ------ Odour identification and ------Odour score - - threshold predictive DLB, PD - conversion from iRBD 44 Table 2 cont. Mondon (2007) Oishi et al Ota et al (2015) Pal et al (2016) Robertson et al Sasai-Sakuma Taylor et al Watanabe (2018) Westervelt (2016) Wood et al Yoo et al (2018) Zarkali et al., (2018) (2016) 2019 et al (2017) (2012) (2013) Visual perception - - DLB ACE-R Visuo- RBD VOSP: Cube - DLB< AD< HC ------DLB=HC analysis VOSP: Silhouettes - DLB< AD= HC - DLB= ------AD=VaD VOSP: - - - DLB> ------DLB=HC Incomplete letters AD VOSP: Object DLB= - - - - decision - - - AD=VaD VOSP: Dot - - - DLB= AD VOSP: Position - - - DLB= VaD>AD DLB= AD=VaD Cog-Pro: Orientation ------ Cog-Pro: visuo- construction ------ Cog-Pro: Perception ------ Dot motion ------ Simple motion ------ Object rotation ------ 45 Gabor contour ------integration MOCA ------ ------Rorschach Block design test ------ MMSE DLB< PDD orientation ------ Benton visual DLB= PDD retention ------ Benton Line - - - - DLB = SVD - DLB DLB Rey complex DLB= PDD - - - DLB= SVD - DLB Overlapping - - DLB Poppelreuter task DLB= PDD ------ Raven’s ------progressive matrices Freidberg Visual Acuity (FRACT) ------ Ambiguous visual ------DLB Illusionary DLB Material (texture) recognition ------ City University DLB< AD< Colour Vision - HC ------Test (CUCVT) Colour test - - - - - DLB Developmental DLB< AD< HC Test of Visual ------Perception (Position in Space) 46 Two-tone Visual ------DLB=AD Animated car ------DLB Auditory Auditory odd-ball ------ Mismatch negativity ------auditory task Olfactory Cross cultural ------DLB Brief smell ------DLB Odour ------identification and threshold 47 Table 3. Results of studies assessing attention-executive functions in DLB patients in comparison to other patient groups and controls. Neuropsychological tasks are sectioned by recruitment of cognitive process as stated in individual studies (attention, executive function, working memory). WAIS = Wechsler Adult Intelligence Scale, CAMCOG = Cambridge Cognition Examination, TMT = trail making test, HC = healthy controls, AD = Alzheimer’s disease, DLB = dementia with Lewy bodies, PD = Parkinson’s disease, PDD = Parkinson’s disease dementia, VaD = Vascular dementia, FTD = frontotemporal dementia, VLOSP = very late onset schizophrenia like psychosis, AD+P = Alzheimer’s disease with psychosis, mDLB= mild DLB, vmDLB = very mild DLB Aldridge Bronnick Crowell Della Elder Firbank Firbank Fuentes Kobeleva Landy et Park Peters Petrova Scullin Taylor Ash et al Cagnin et Marchand et Petrova et al Van Assche et al et al et al Sala et al et al et al et al et al al (2015a) et al et al et al et al et al Watson et al (2012) al (2012) al (2016) (2016) (2018) (2018) (2016) (2007) (2012) (2016) (2016) (2018) (2010) (2017) (2011) (2012) (2015) (2012) (2013) (2017) Attention DLB= DLB WAIS-III Digit Span DLB= DLB< DLB< DLB< DLB=AD+P= PDD< DLB= AD DLB=PD WAIS-III Digit Span DLB< DLB=AD+P= DLB= Forward PD VLOSLP ------PDD - - - DLB< WAIS-III Digit Symbol AD Benton Visual Retention DLB= PDD ------ DLB= AD Digit cancellation ------ Attention Network Task (ANT) DLB=AD DLB DLB< DLB=AD CAMCOG executive DLB=AD AD< HC =HC ------ CAMCOG attention DLB< ------AD - Choice Reaction Time DLB Letter cancellation ------DLB< Rapid Serial Visual AD< Presentation Task ------HC ------ 48 DLB DLB DLB DLB=AD Simple visual search task =PD=HC ------ Feature conjunction search DLB Executive DLB< DLB= AD< DLB= DLB< DLB= mDLB< TMT-B PDD< DLB DLB< DLB= TMT-A DLB< AD DLB< AD DLB WAIS-II Similarities DLB= PDD ------ DLB=PD DLB Controlled Oral Word Association Test (COWAT) ------ DLB= Category fluency DLB= PDD< DLB= AD - - AD 49 DLB= DLB= PDD< DLB= mDLB< Stroop DLB< AD PDD< - PD= HC ------PDD vmDLB - - - - AD DLB=HC >AD Boston Naming Test ------ DLB> Working memory AD< FTD< Prose memory (immediate DLB> AD - - - - VaD= ------recall) PD - Word list recall ------DLB=AD ------ Memory and executive screening ------ DLB= AD< Object-colour binding task - - - - - VaD= ------PD= - - FTD DLB= AD= Digit Span - - - - - VaD> ------FTD< PD 50 51