Idiopathic REM sleep behavior disorder and olfactory dysfunction in Parkinson's disease and premotor stages. MRI and neuropsychological studies

Abstract

BACKGROUND:

The present Doctoral Thesis is focused on Rapid-eye-movement (REM) sleep behavior disorder (RBD) and olfactory dysfunction as biomarkers of Synucleinopathies, such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). RBD is a parasomnia characterized by loss of atonia during REM sleep that provokes dream-enacting behaviors. Clinically isolated RBD (IRBD) is considered a prodromal stage of alpha-Synucleinopathies since almost 75% of patients after 12 years of the disease develop a PD or atypical parkinsonism. Specifically, in a multicentric study, 56.5% of IRBD patients converted to parkinsonism as the first manifestation, while 43.5% developed dementia first. Subtle motor symptoms, hyposmia, and cognitive impairment are the best predictors of phenoconversion in IRBD.

OBJECTIVES AND HYPOTHESES:

The main objectives of this Thesis are: 1) To characterize structural and functional brain substrates underlying Idiopathic REM sleep behavior disorder as well as to relate these findings to cognitive performance; 2) To study olfactory dysfunction as a preclinical and clinical biomarker of alpha- Synucleinopathies, and its progression throughout the disease; 3) To investigate progressive brain degeneration throughout IRBD, and to investigate how these changes relate to cognitive decline. The main hypotheses are:

1) IRBD will be characterized by specific changes in brain structure and functional connectivity that will be associate with olfactory and cognitive impairment, 2) IRBD patients will show structural brain changes over time and a cognitive decline superior to that seen in normal aging, 3) Smell dysfunction will be identified in IRBD and PD, and it is expected to progress slightly with the disease course.

MATERIAL AND METHODS:

This Doctoral Thesis is presented as a compendium of six studies that were carried out to achieve the above-mentioned objectives.

RESULTS:

In studies 1, 2, and 5, IRBD patients differed from controls in several cognitive domains, namely attention and executive functions, mental processing speed, verbal memory, and semantic fluency. Besides, studies 1 and 5 identified for first-time impairment in facial recognition and visuospatial functions. Contrary to our hypothesis in study 1, we did not find significant correlations between cognitive performance and brain atrophy. However, there was coherence between the structural changes detected by MRI and neuropsychological impairment. For instance, IRBD subjects had facial recognition impairment and cortical atrophy in the fusiform gyrus, a region that is known to be critical for such function. In the same way, patients showed memory impairment and hippocampal atrophy, a core structure for learning and memory. On the other hand, study 2 evidenced the potential role of altered brain functional connectivity in IRBD’s cognitive impairment. We found a positive correlation between mental processing speed and temporoparietal functional connectivity in the IRBD group. In study 5, we reported visual form discrimination decline in IRBD relative to normal aging after less than two years. More importantly, we identified that visual form discrimination worsening over time was explained by progressive reductions of the cortical thickness in the superior parietal.

CONCLUSIONS:

The present Doctoral Thesis has identified new cognitive deficits in IRBD patients and has shed some light on its progression throughout the course of the disease. In particular, our work has shown the importance of VS/VP functions as a measure able to identify cognitive changes across time in IRBD, and its potential in identifying those patients with progressive neurodegeneration in posterior cortices. Besides, we have exhaustively described the characteristics of severe and early olfactory dysfunction in IRBD and described for the first time its neuroanatomical correlates. The neuroimaging data from this Thesis points towards an early implication of the temporal-occipital-parietal cortices in IRBD. Additionally, our longitudinal work has shown that IRBD patients have brain degeneration of the occipitoparietal and orbitofrontal cortex over time, in line with the degenerative changes reported in PD and DLB. Abnormalities in such regions are supported by the association between impaired cognition and both functional and structural brain changes.

Cortical atrophy and disrupted cortico-cortical functional connectivity highlight that cortical degeneration and functional abnormalities already exist in patients with IRBD before they are diagnosed with DLB, PD, or MSA. Thus, suggesting that in prodromal PD, the alpha-synuclein pathology is already involving these structures earlier than would be expected according to the Braak degeneration model proposed form neuropathological data. Cortical atrophy and dysfunction may explain why some patients present neuropsychological impairment before the motor onset. We hope that our research will serve as a basis for further multicentric studies that confirm our findings, and to identify the optimal neuropsychological and neuroimaging markers for diagnostic, prognostic, and efficacy of future neuroprotective therapies.

MARC TEÒRIC:

La present Tesi Doctoral estudia el trastorn del comportament del son REM (RBD, per les seves sigles en anglès) i la disfunció olfactiva com a biomarcadors de les alfa- Sinucleinopaties, com ara la malaltia de Parkinson (PD, per les seves sigles en anglès), la demència per cossos de Lewy (DLB, per les seves sigles en anglès) i l’atròfia multisistèmica (MSA, per les seves sigles en anglès). El RBD és una parasòmnia caracteritzada per la pèrdua d’atonia durant el son REM que provoca episodis on els pacients mostren moviments que reflecteixen el contingut dels seus somnis. El RBD que es presenta clínicament aïllat (IRBD, per les seves sigles en anglès), es considera un estadi prodròmic de les Sinucleinopaties, doncs s’ha vist que gairebé el 75% dels pacients després de 12 anys amb diagnòstic d’IRBD acaben sent diagnosticats de malaltia de Parkinson o parkinsonismes atípics. Concretament, en un estudi multicèntric el 56.5% dels pacients amb IRBD varen desenvolupar parkinsonisme com a primera manifestació, mentre que el 43.5% va presentar demència en primer lloc. La simptomatologia motora, la hipòsmia i el deteriorament cognitiu han demostrat ser els millors predictors de conversió en aquests pacients. En aquest context, la comunitat científica ha demostrat un interès creixent en definir els canvis cognitius associats a l’IRBD. Els estudis publicats fins ara conclouen que entre el 15-50% dels pacients tenen deteriorament cognitiu lleu. Malgrat l’evidència ben documentada sobre la presència d’afectació neuropsicològica en pacients amb IRBD, cal una recerca addicional que valori de forma aïllada i específica les funcions visuoespacials i visuoperceptives (VS/VP), ja que l’alteració d’aquestes funcions és característica del perfil neuropsicològic dels pacients amb PD i DLB. Pel que fa al declivi cognitiu al llarg de la malaltia, encara hi ha una gran incertesa.

OBJECTIUS I HIPÒTESIS:

Els objectius principals d'aquesta Tesi són: 1 Caracteritzar els substrats cerebrals estructurals i funcionals subjacents a l’RBD, així com relacionar aquestes troballes amb el rendiment cognitiu, 2 Estudiar la disfunció olfactiva com a biomarcador clínic i preclínic de les alfa- Sinucleinopaties, i la seva progressió al llarg de la malaltia, 3 Investigar la degeneració cerebral progressiva al llarg de l’IRBD i com aquests canvis es relacionen amb el declivi cognitiu. Les principals hipòtesis són: 1 L'IRBD es caracteritzarà per canvis específics en l'estructura cerebral i la connectivitat funcional que estarà associada a un deteriorament olfactiu i cognitiu, 2 Els pacients amb IRBD mostraran canvis cerebrals estructurals amb el pas del temps i un declivi cognitiu superior a l’observat en l’envelliment normal, 3 S'espera identificar reducció de la capacitat olfactòria en l'IRBD i la PD, així com que progressi lleugerament amb el curs de la malaltia.

MATERIAL I MÈTODES:

La present Tesi Doctoral consta de sis estudis realitzats per donar resposta als objectius esmenats anteriorment. CONCLUSIONS:

La present Tesi Doctoral ha identificat nous dèficits cognitius en pacients amb IRBD i ha perfilar la seva progressió al llarg de l’evolució de la malaltia. En particular, el nostre treball ha demostrat la importància de les funcions VS/VP com a mesura capaç d’identificar els canvis cognitius a través del temps en l’IRBD i el seu potencial per identificar aquells pacients amb neurodegeneració progressiva en el còrtex posterior. A més, hem descrit de forma exhaustiva les característiques de la disfunció olfactiva precoç i greu de l’IRBD i hem descrit per primera vegada els seus correlats neuroanatòmics.