Future directions - The sleep-wake abnormalities in DLB challenge the study of sleep in this d

The sleep-wake abnormalities in DLB challenge the study of sleep in this disease

6.6. Future directions

Here I propose the questions that go beyond this thesis and that will need future research. To validate the three clinical subtypes of DLB a study of the

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ferences that may relate to the different phenotypes. Most of the neuropatho-logical studies addressing the clinical variety in DLB centred in the presence of AD copathology (65,93). To properly understand the contribution of AD copathology and other copathologies, as TDP-43 aggregates, in these clusters, neuropathological studies aimed to quantify these copathologies in the differ-ent cortical and subcortical brain areas in DLB patidiffer-ents with extensive and de-tailed clinical reports from the stage of MCI are needed. On the other hand, a neuropathological study of DLB patients subdivided according to the proposed clinical subtypes would also allow the study of the cellular and molecular bi-ology beyond the Lewy body related pathbi-ology and AD copathbi-ology that may underlie the clinical heterogeneity in DLB. New techniques assessing the dif-ferent pointed α-synuclein strains and specific seeding capacity as well as their relationship with tau aggregation should be applied in the research of the clin-ical heterogeneity, not merely along synucleinopathies, but within DLB itself.

The development and application of biochemical and neuroimaging bio-markers is highly relevant to disentangle the biological basis supporting the clinical heterogeneity in DLB. These markers would be essential in the detection of the prodromal phase of DLB. The recognition of prodromal DLB is highly relevant considering future disease-modifying drugs that may be more effective in this phase of the disease. The study of DLB patients from their earlier stages would allow longitudinal studies to investigate the evolution of the biological markers together with the different clinical features. Although iRBD patients are amenable to longitudinal follow-up (107), to avoid biases in extrapolating features typical from those patients to others without RBD and that may present very different characteristics (107), such studies should not be limited to this group.

Furthermore, studies aimed at exploring the relationship between the brain structure and function by MRI and the three clinical subtypes presented in

Chapter III are needed. This study could be complemented with functional neuroimaging based on PET scan, which would also be informative of the underlying damage to neural networks underlying the proposed clinical sub-types. New neuroimaging technics as amyloid- and tau- PET could also be useful to study copathology and pathological synergies in DLB. To obtain this objective, larger cohorts with appropriate and quantified neuroimaging examinations and a complete and prospective clinical assessment from the stage of MCI, are required. Since DLB has a lower prevalence and incidence than AD, and is frequently underdiagnosed, the creation of large, sufficiently powered cohorts to perform different studies is challenging. To solve this problem, it is crucial to create and enlarge common and public repositories based on multicentric and international recruitment following the example of the Alzheimer Disease Neuroimaging Initiative (ADNI). With this aim, sev-eral initiatives such as the European DLB consortium in Europe or the De-mentia with Lewy bodies Consortium in United States have started recently.

From a clinical point of view, the importance of the V-PSG in the study of the sleep disturbances in DLB has been highlighted in Chapter IV. Larger studies with a systematic V-PSG analysis aimed to establish new descriptive criteria for the assessment of sleep in demented patients, specifically in DLB, are needed. These criteria would help in the harmonization of sleep stud-ies focused on better understanding the sleep pathology in DLB. Improved systematic and specific studies of sleep disturbances in DLB in specialized clinical centres improves the clinical management of these patients. Given the limited access and the difficulties associated with performing a V-PSG on demented patients, the search for other early markers that can identi-fy candidates who would benefit from V-PSG would be of help in clinical practice. How the different sleep pathologies in DLB correlate with specific phenotypes, biomarker profile and underlying neuropathology should also

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Finally, neuropathological and experimental studies using cellular and ani-mal models and aimed at understanding the role of glial activation in DLB should be undertaken. Specifically, in vitro and in vivo studies of how glial activity influences tau pathology in synucleinopathies should be performed.

Besides basic experimental studies, we should consider the importance of neuropathological studies specifically aimed to better understand the role of glial cells in the human DLB brain. Specific studies aimed at unravelling the role of glial cells in the beginning and the evolution of the DLB are needed.

7. CONCLUSIONS

• Three subtypes of DLB that differ in their clini-cal manifestations and progression can be distin-guished based on the predominant symptoms dur-ing the prodromal phase of the disease: cognitive-, psychotic- and parkinsonism-predominant.

• Sleep-wake disturbances are common and com-plex in patients with DLB. V-PSG is essential to di-agnose RBD and rule out mimics.

• DLB and AD show different patterns of glial

acti-vation markers in CSF. sTREM2, PRGN and YKL-40

levels in CSF are normal in prodromal DLB and DLB

in the absence of AD co-pathology. YKL40 levels are

only elevated in those DLB patients with abnormal

core AD biomarkers.

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