The importance of recognising the prodromal phase of DLB

The main strength of this thesis is the emphasis on characterizing the prodro-mal phase of DLB. The lack of diagnostic consensus criteria for this stage is an unmet urgent need in DLB research. The study of the prodromal phase of DLB has been possible thanks to the prospective recruitment of a prospective DLB cohort, including MCI patients with features suggestive of an

under-lying synucleinopathy that have been followed up over several years until they met the diagnostic criteria for DLB. In chapter III we demonstrated the relevance of this stage for recognising the different clinical subtypes. From a physiopathologic point of view, chapter V shows a lack of elevation of glial markers in the prodromal stage that suggests a differential role of glial cells in DLB with respect to AD. In chapter IV we stated that monitoring the sleep disturbances enables the recognition of the prodromal stage of DLB as, when present, they may be present years before the diagnosis of DLB.

The three clinical subtypes described in this thesis clearly support the no-tion that clinical heterogeneity is greater during the prodromal, rather than dementia, stage. The clinical features present during this phase may cap-ture better the initial topography of neuronal dysfunction and loss as well as better reflect the heterogeneity existing in DLB (117,193,194). As the disease progresses, the more severe and widespread pathology may result in a more homogeneous syndrome. This greater heterogeneity during the prodromal phase of DLB importantly challenges the homogenization of di-agnostic criteria during this phase, challenging its recognition (109,110).

Another important challenge to the identification of prodromal DLB is the lack of suitable biomarkers to reflect the underlying physiopathological processes, namely the deposition of α-synuclein and formation of Lewy bodies. The need for good biomarkers applicable to the prodromal phase of DLB is emphasized by one of the main results of chapter III, the existence of a cognitive-predominant subtype that partially overlaps with prodromal AD. This cognitive-predominant subtype, characterised by the dominance of isolated cognitive impairment during the first years of the disease and a slow progression, is the most common form of prodromal DLB in our cohort. This cluster partially overlaps with the typical amnestic MCI due

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markers. In fact, previous clinicopathological studies have highlighted the importance of considering DLB in the differential diagnosis of MCI, as a subset of subjects will convert to DLB during follow-up (110). Nowadays CSF biomarkers are helpful in identifying those MCI patients with under-lying AD pathology related to their clinical syndrome and thus, allowing a diagnosis of prodromal AD. However, currently this is not possible in DLB, due to the lack of biochemical markers of Lewy body related pathol-ogy. Moreover, considering the high prevalence of AD copathology in DLB, it would be possible that a prodromal DLB patient had a CSF biomark-er profile suggestive of AD undbiomark-erlying pathology. Thus, the diagnosis of prodromal DLB is obscured by the existence of biomarkers of AD and the absence of biomarkers for Lewy body related pathology. The development of specific and sensitive CSF and/or neuroimaging biomarkers for Lewy body-related pathology in the initial stages of the disease is essential to the correct clinical management of MCI.

Definition of the prodromal phase of DLB may be crucial to distinguish DLB cases when diagnosis is uncertain (50). With that aim, chapter III provided a detailed clinical description of prodromal DLB. This has been possible be-cause of a structured chart review and the performance of a questionnaire specifically oriented to the identification of the main clinical features in DLB and a complete neuropsychological assessment. It is important to re-mark that all cognitive domains, and not only memory, should be assessed in MCI patients to allow the correct recognition of prodromal DLB, as atten-tion and visuospatial domains are typically affected while memory is often preserved. This consideration is important, especially in those patients with iRBD, an important group at risk of developing DLB. The assessment based on screening tools, such as MMSE, can result in an underdiagnosis of DLB in its prodromal stage because of its lack of sensitivity to detect the earliest phases of DLB as is the case of MCI due to AD (14,111).

Chapter IV highlighted the importance of sleep disturbances in DLB. Sleep abnormalities, such as RBD symptoms, are especially relevant in prodromal DLB since when present, may precede cognitive symptoms and the full-blown picture of DLB by several years. Chapter IV also described other EEG features, such as the slow occipital rhythm, which enables identification of patients more susceptible to RBD. This finding could be useful in MCI patients as this may be useful to select candidates for a more detailed sleep study, facilitating the recognition of RBD and other sleep disturbances in DLB.

6.5. Limitations

The main limitations common to the three studies included in this thesis are the relatively small number of included patients, the lack of pathological confirmation of the DLB diagnosis and that the entire cohort was recruited in a single center that can result in some biases, such as selection bias, etc.

There is also need to validate the results in an independent cohort.

Besides these common limitations, there are other specific limitations for each sub-study. In chapter III, part of the data was collected retrospectively and, due to the low number of patients who had CSF biomarkers or brain imaging, study of these biomarkers was not feasible. The main limitations in chapter IV were that more than 50% of the patients refused to partici-pate; some patients did not achieve enough REM sleep, there was not a reli-able sleep informant in 51% of cases, some patients used medications that could modify the sleep architecture, and a control group was not included.