1. CHAPTER I: INTRODUCTION
1.2. Dementia with Lewy Bodies from a clinical point of view
1.2.2. Biomarkers in Dementia with Lewy bodies
The main changes between the current clinical diagnostic criteria and the previous ones published in 2005 is a clear separation between clinical fea-tures and biomarkers, and an emphasis on the importance of RBD in the
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Although there is no available biomarker to reflect Lewy body pathology, several other biomarkers are used in research studies and clinical practice.
Moreover, in accordance with the new clinical diagnostic criteria for DLB, we can even state a diagnosis of DLB based on indicative biomarkers in the absence of any core clinical feature (13). The more clinical relevant bio-markers according to the last consensus diagnostic criteria are:
1.2.2.1. Indicative biomarkers.
Video-polysomnography (V-PSG). The demonstration of RBD or REM sleep without atonia is highly specific of an underlying synucleinopathy (22,23). As a result, the presence of a confirmative V-PSG alone is enough to make a diagnosis of DLB in a patient with dementia in the absence of any other core feature or biomarker (13). The following section and Chapter IV will address the relevance of this test in more detail.
Dopamine transporter (DAT) imaging. A decreased DAT uptake in basal ganglia, demonstrated by SPECT and PET imaging, can differentiate DLB from AD with a sensitivity and specificity of 78 and 90% respectively (24).
It can also rule out the possibility of other overlapping syndromes, such as MSA, progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD) (25,26). Nevertheless, normal DAT imaging is also possible as a re-sult of symmetrical and balanced damage to the whole striatum rather than asymmetrical and predominant uptake reduction in the putamen (25,26).
There are also DLB patients with a scarce brainstem involvement and low nigral neuronal loss that may result in a normal DAT imaging (27).
Figure 3. A: Abnormal DaTScan imaging showing bilateral and symmetric decreased DAT uptake in a DLB patient. B: MRI imaging showing the relative preservation of MTL structures in DLB.
Metaiodobenzylguanidine myiocardial scintigraphy (123Iodine-MIBG).
Reduced uptake of 123Iodine-MIBG, a sign of damage to the postganglionic sympathetic cardiac innervations (13), is present in PD and DLB but not in AD, MSA, PSP or CBD. That being said, the high prevalence of other comor-bidities in the elderly, such as diabetes mellitus or ischemic heart disease, as well as frequently prescribed medications that can alter the result of the test, thus reducing the clinical relevance of this biomarker (28).
1.2.2.2. Supportive biomarkers
Functional neuroimaging. Occipital hypometabolism demonstrated by 18F-Fluorodeoxiglucose positron emission tomography (FDG-PET) suggests a diagnosis of DLB rather than AD and correlates with visual cortex dam-age with a sensitivity and specificity of 70 and 74% respectively (29–31).
The cingulate sign is described as the relative preservation of posterior or mid-cingulate cortex and is characteristic of DLB (32), correlating with
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Structural neuroimaging. The relative volume preservation of medial temporal lobe (MTL) evidenced by magnetic resonance imaging (MRI) or computerized tomography (CT) is suggestive of DLB when compared to AD. However, MTL atrophy is possible in DLB and may indicate higher AD copathology and faster cognitive decline (34).
Electroencephalography (EEG). A prominent posterior slow-wave EEG activity together with the possible presence of alpha/theta/delta activities in pseudoperiodic patterns is characteristic of DLB. It has a positive pre-dictive value higher than 90% and correlates with the severity of clinical fluctuations. However, this EEG pattern may be rare in MCI stage (13).
1.2.2.3. Fluid biomarkers
Even when a diagnostic marker for DLB, either in blood or CSF, remains elusive, some biomarkers have been studied in these fluids in DLB. Con-cerning blood markers, an increase in the albumin CSF/serum ratio has been shown in DLB patients, but also in PDD and in stroke patients as a result of damage to the blood-brain barrier that is typical in these diseases (35). Higher plasma levels of annexin A5, a calcium and phospholipid bind-ing protein, and transthyretin protein, which is involved in amyloid β (Aβ) clearance and maybe also involved in α-synuclein clearance, have been described in DLB, but also in AD (36,37). Blood markers for endothelial cell activation have also been reported to be altered in DLB and AD (38).
Several studies have also failed to find specific biochemical markers for Lewy-related pathology in CSF. As the main component of Lewy related pa-thology, α-synuclein has been proposed as a potential biochemical marker for diagnosing DLB (39). The role of α-synuclein is not completely under-stood, but it may be involved in neurotransmitter release, vesicle traffick-ing, synaptic plasticity, brain lipid metabolism and membrane remodelling
(39,40). Previous studies have shown that the CSF levels of α-synuclein are decreased in PD and DLB and increased in AD and CJD (41,42). These find-ings suggest that this protein may not only be a marker of underlying synu-cleinopathy, but also a marker for synaptic damage and neurodegeneration (39,43). Thus, the diagnostic utility of CSF α-synuclein in DLB is limited (44). The levels of different species of α-synuclein have also been investi-gated in DLB and PD, mainly alpha synuclein phosphorylated at Serine 129 (p-α-synuclein) and oligomeric α-synuclein (o-α-synuclein) (42,45,46). An increase in CSF oligomeric α-synuclein has been described in DLB and PDD compared to AD (45). A recent study also showed a relative increase in its clinical utility when CSF total α-synuclein was combined with CSF total tau (44). Other combinations of several markers from diverse origins have been proposed to enhance the diagnostic accuracy of α-synuclein (47).
Nevertheless, none of the described biomarkers are specific for DLB, and are usually common to AD and PD. Thus, the search for specific diagnostic markers for DLB that reflects the underlying pathophysiology is a research priority in the field of neurodegenerative dementias.
Core AD CSF biomarkers (Aβ40, Aβ42, t-tau and p-tau) have also been in-vestigated in DLB. Different studies have correlated these AD markers with different clinical features in DLB, such as the presence of visual hallucina-tions or a faster cognitive decline (48). Additionally, AD core biomarkers can be useful in the clinical assessment of DLB, as CSF levels of tau and Aβ can detect those DLB patients with a higher burden of cortical Lewy body related pathology. Thus, these biomarkers can have important implications in prognosis and, when available, in the selection of individuals who could benefit from the administration of specific disease-modifying treatments that target both α-synuclein and Aβ (49).
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