Dementia with Lewy bodies from a neuropathologic perspective

1.3.1. Definition and current neuropathologic diagnostic criteria

Pathologically, DLB is defined by the presence of intraneuronal inclusions known as Lewy bodies (LB) and Lewy neurites (LN), which are also hall-marks of PD (11,13). In 1997, Spillantini et al discovered that the main component of these inclusions was α-synuclein (10). In DLB, α-synuclein is thought to spread inward from the olfactory bulb towards neocortical and lower brain areas, which contrasts the PD in which α-synuclein pathology is proposed to start in the brainstem and follow an ascendant spreading (50). The transmission α-synuclein from cell to cell of via endocytosis has been reported in cell models. In those models, dysfunctional quality control systems, particularly in lysosomes, promoted the formation of α-synuclein intracellular inclusions in the form of Lewy bodies or Lewy neurites (51).

The presence of Lewy bodies and neurites together with a compatible clinical syndrome during life are required for a pathologic confirmation of the DLB diagnosis (13). Alzheimer´s disease (AD) related pathology is a common comorbid pathology in most patients with a pathological DLB diagnosis (52).

Considering this frequent AD copathology, the pathological diagnosis of DLB is based on the probability that the suggestive clinical syndrome is due to α-synuclein pathology, AD pathology or a combination of both. The patholog-ical diagnostic criteria of DLB are summarized in table 2 (13)

Table 2. Likelihood that the clinical syndrome is due to Lewy-related pathology. Based on the patholog-ic diagnosis scheme published by McKeith et al Neurology 2017.

AD PATHOLOGY

Olfactory bulb only Low Low Low

Substantia Nigra neuronal loss should be assessed as none, mild, moderate and severe to classify cases according to the probability of having parkinsonism

1.3.2. Common AD copathology

AD pathology in DLB tends to be more frequent in entorhinal cortex, amygdala and putamen (53). The percentage of patients with a diagnosis of DLB and AD copathology reported in the literature varies depending on whether the studies have been based on a pathological or clinical cohort and, in the latter, the method used to detect the suspected AD copathol-ogy. In neuropathological series, the percentage of DLB patients that also present sufficient AD copathology for a secondary pathologic diagnosis of AD is around a 50% (49,54). However, if we consider the presence of any degree of Alzheimer pathology, roughly 86% of pathologically confirmed DLB cases have AD copathology (55). By definition, neuropathological studies usually investigate end stage dementia. Therefore, these studies likely overestimate the contribution of AD copathology to the DLB phe-notype. This overestimation may be more evident during the first years of the disease especially when considering the synergistic effect of AD and Lewy-related pathologies that will be more profoundly explained later in this section.

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In vivo studies are essential to better understand the contribution of AD copathology to the clinical phenotype in DLB. Nowadays, Alzheimer’s pa-thology can be studied in clinical cohorts using the core AD biomarkers in CSF and by amyloid imaging. Based on clinical cohorts in which AD copa-thology was investigated by amyloid imaging we know that concomitant Alzheimer’s pathology depends on the age and the APOE genotype in DLB patients (56). APOE ɛ4 is a known genetic risk factor for AD (57), but also for α-synuclein pathology independently of AD copathology (58,59). Thus, AD copathology varies from 63% at 60 years old to 83% at 80 years old in APOE ɛ4 carriers DLB patients, and from 29% at 60 years old to 54% at 80 years old in noncarriers (56). In clinical a cohort studied by CSF biomark-ers, the percentage of AD copathology suspected by a suggestive biomarker profile is 38% (48) But the variation can be high as it depends on the clini-cal cohort studied (older patients from a Geriatric Unit or younger patients from Sleep or Movement disorders clinics).

Figure 4. The AD copathology in DLB: Lewy bodies and Lewy neurites representing Lewy related pa-thology and neurofibrilary tangles and neuritic plaques representing AD copapa-thology. Neuropathologic images courtesy of Marti Colom-Cadena.

In pathological series, the misdiagnosis of DLB, usually as AD, increases up to 50% (60), and is even higher when the cortical extension of α-synuclein is lower and the neuritic plaque burden is higher (61). Thus, the neuro-pathological diagnosis is crucial to properly detect DLB, the dementia most often misdiagnosed as other diseases (62).

Lewy related pathology Neurofibrilary tangles and amyloid plaques

1.3.3. Interaction between AD and Lewy pathologies

A synergistic effect between AD and Lewy pathologies has been proposed in DLB. Tau and α-synuclein pathology often colocalize in limbic areas, a brain area that has been proposed as an incubator for the spreading of misfolded proteins (63,64). Neuropathological studies have shown that the burden of tau pathology is one of the main factors related to the amount of cortical α-synuclein deposits (49,65). This is supported by other studies in which core AD biomarkers in CSF have been proposed as predictors of cortical α-synu-clein (54). Cell culture studies have also investigated the synergistic effect between tau and alpha synuclein, finding that both misfolded proteins act together enhancing the cellular dysfunction and death (66). A shared seeding effect between α-synuclein, Aβ40 and Aβ42 has also been observed in vitro, with α-synuclein being attributed the increased seeding potential of the three (67). Thus, the interaction between these three misfolded proteins may con-tribute to increased seeding, cellular dysfunction and death and possibly to the trans-synaptic spread of both Lewy body and AD related pathologies (49).