par Segers, Kurt
Président du jury Schiffmann, Serge N.
Promoteur Surquin, Murielle
Co-Promoteur Hambye, Anne Sophie
Publication Non publié, 2025-05-13
Thèse de doctorat
Résumé : Résumé en françaisLa maladie à corps de Lewy (MCL) est fréquemment sous-diagnostiquée, bien qu'elle constitue la deuxième cause de démence d’origine neurodégénérative après la maladie d'Alzheimer (MA). Cliniquement et pathologiquement (accumulation d'α-synucléine), la MCL se rapproche davantage de la maladie de Parkinson (MP) que de la MA.La MCL se caractérise par quatre signes et symptômes cardinaux : des hallucinations visuelles récurrentes, une fluctuation cognitive marquée, des perturbations du sommeil paradoxal (REM) et un parkinsonisme.Dans le cadre de notre travail, nous avons contribué à l'amélioration du diagnostic de cette maladie en développant un test rapide permettant de détecter les fluctuations cognitives, sans nécessiter la présence d’un aidant proche. Nous avons également mis en évidence que l’anxiété importante (nécessitant une aide médicale), est un symptôme plus fréquent chez les patients atteints de MCL, comparativement aux patients atteints de MA ou aux sujets âgés témoins.En observant les patients atteints de MCL dans notre clinique de la mémoire, nous avons noté que la prévalence de ce diagnostic était deux fois plus élevée chez les patients d’origine nord-africaine que chez les patients provenant d’autres groupes ethniques, suggérant le rôle potentiel d’une prédisposition génétique dans cette population. Plus précisément, nous avons envisagé la mutation G2019S du gène LRRK2, qui est la cause génétique la plus fréquente de la MP, et qui concerne environ 1,5 % de la population maghrébine. Deux études génétiques précédentes avaient conclu que cette mutation ne jouait aucun rôle dans la MCL, mais ces études ne portaient que sur des patients d’origine occidentale.Dans notre étude, nous avons identifié cette mutation chez 5 des 47 patients MCL ayant des ancêtres nord-africains, soit une prévalence de 10.6%, 7 fois plus élevée que celle observée dans la population générale maghrébine. Nous avons ainsi mis en évidence une quatrième cause génétique de la MCL, après les mutations des gènes APOE (codant l’apolipoprotéine E), GBA1 (codant la β-glucocérébrosidase) et SNCA (codant l’α-synucléine). Cette découverte revêt une grande importance, car des traitements ciblant LRRK2 sont actuellement à l’étude pour la MP. De plus, nos travaux soulignent la nécessité d'inclure des patients d’origines ethniques diverses dans les études cliniques pour une meilleure compréhension des pathologies. Global summaryLewy Body Disease (LBD) is after Alzheimer’s disease the second most common neurodegenerative cause of dementia. It is hallmarked by 4 cardinal symptoms: recurrent visual hallucinations, marked fluctuations in attention and cognition, REM-sleep behavior disorder and parkinsonism, though not all patients will develop all symptoms. This underdiagnosed disease shares so much characteristics with Parkinson’s disease (PD) that both are probably clinical manifestations of a disease spectrum with the same underlying pathology (synucleinopathies), namely the accumulation of α-synuclein and intraneuronal Lewy bodies. The diagnosis of LBD (without or with dementia) is based on clinical criteria worked out by the DLB Consortium which are regularly revised. Diagnosis can be made if the patient presents at least 2 out of 4 of the above-mentioned cardinal symptoms, or only 1 criterion with at least one abnormal biomarker (reduced dopamine transporter uptake in basal ganglia demonstrated by cerebral ioflupane Single Photon Emission Computerized Tomography (SPECT) or Positron Emitting Tomography (PET), polysomnographic confirmation of REM sleep without atonia , abnormal (low uptake) on 123I-MIBG myocardial scintigraphy).Working in as a neurologist at the Memory Clinic of the Neurology and Geriatrics Department of the Brugmann University Hospital in Brussels, which has a database of more than 4000 patients coming from more than 80 different countries, I became interested in the diagnosis of LBD in immigrants.Question 1 : Do pathologies that lead to dementia have the same frequency in the first generation immigrant population of a Memory Clinic compared to patients born in Belgium ? • A first retrospective study of the Memory Clinic’s patients between 2005 and 2012 suggested that European immigrants were more likely to develop LBD or PD compared to patients born in Belgium. A similar tendency was observed for North African patients but did not reach statistical significance. Article: Pioneers in migration, pioneering in dementia: first generation immigrants in a European metropolitan memory clinic. K Segers, F Benoit, C Colson, V Kovac, D Nury, V Vanderaspoilden. Acta Neurologica Belgica 2013 ; 113 (4), Question 2 : Are certain groups of immigrants more at risk of developing a synucleinopathy? • Our second retrospective study focalized on LBD. It showed that first generation immigrants consulting our Memory Clinic were twice more likely to receive a LBD diagnosis, a phenomenon explained by a higher prevalence of LBD amongst our patients from North Africa and South America. Article: Dementia with Lewy bodies in first-generation immigrants in a European memory clinic. K Segers, F Benoit, JM Meyts, G Glibert, S Levy, M SurquinActa Neurologica Belgica 2021;121 (1), 219-223At the same time, we have tried to improve diagnosis of LBD given the difficulties of using and interpreting classical neurological tests with immigrants (language barrier, absence of formal schooling) and the difficulties of detecting parasomnia and cognitive fluctuation in patients who often live alone, or at least come to the hospital without an informant. Question 3 : What was the impact of the last revision of the diagnostic criteria for LBD (2017) compared to the criteria of 2005?• A retrospective analysis of our database suggests that the last set of criteria has a higher sensibility thanks to its incorporation of parasomnia and of the results of ioflupane scans: of the 92 patients diagnosed with the 2017 criteria, four would not have been diagnosed with the 2005 criteria.Article : A direct comparison of the 2005 and 2017 criteria for dementia with Lewy bodies. K Segers, F Benoit, JM Meyts, G Glibert, M Surquin. Psychogeriatrics 2020. 20 (5), 785-786.Question 4 : Could anxiety be a novel criterion for the diagnosis of LBD? • We retrospectively matched 41 patients with LBD to 41 patients with Alzheimer’s disease (AD). We observed that anxiety but not depression was more frequent with DLB than AD (63.4% vs 26.8%). Anxiety in LBD appeared 4 to 5 years before diagnosis and was more intense than anxiety linked to AD, resulting in more visits to an emergency ward and psychiatric consultations/hospitalizations.Article : Anxiety symptoms are quantitatively and qualitatively different in dementia with Lewy bodies than in Alzheimerʼs disease in the years preceding clinical diagnosis. K Segers, F Benoit, JM Meyts, M Surquin. Psychogeriatrics 2020 ; 20(3), 242-246.Question 5 : Can we develop a quick and easy bedside test to detect cognitive fluctuation, even in the absence of a caregiver ? • In a prospective study, we repeated a forward and backward digit span test after a 20 minutes interval to document cognitive fluctuation in patients with LBD, with AD and in elderly persons without cognitive problems. We observed that cognitive fluctuation was more frequent in the LBD group (70% vs < 10% for both other groups. The isolated interpretation of the test result permitted to predict with a precision of 83% if a test person was in the LBD group (sensitivity : 70%, specificity: 90%). Compared to the use of questionnaires for cognitive fluctuation, this method does not require the presence of a caregiver, which is a major advantage. Article: A short and simple bedside test to detect cognitive fluctuations in patients with dementia with Lewy bodies. Segers K, Benoit F, Oliveira Rocha F, Praet JP, Surquin M. Acta Neurologica Belgica 2023; 123 (3), 803-806.Question 6 : Does the G2019S mutation of the gene LRRK2, involved in PD in North-Africans, also play a role in North Africans with LBD?• Until now, three genes have been associated with LBD, namely APOE coding for apolipoproteinE, GBA1 coding for β-Glucocerebrosidase and SNCA coding for α-synuclein, the major protein that accumulates in Lewy bodies. However, mutations of more genes are associated with PD, one of them being the gene for Leucine Rich Repeat Kinase 2 (LRRK2). Mutations in the LRRK2 gene are even the most common genetic cause of Parkinson’s disease, but are believed to play no significant role in LBD . As the frequency of a particular LRRK2 mutation called G2019S, is extremely high in North-African PD patients, we postulated that the high prevalence of LBD in North-Africans might be due to the same mutation. 162 patients were tested for the mutation, which was present in 5 of the 47 patients with North-African ancestors. This is a much higher prevalence (10.6%) than in healthy North-African subjects (1.45%), but lower than in North-African Parkinson’s patients (36-39%). Carriers tended to develop more often orthostatic hypotension and swallowing problems. Where previous studies in European and North American patients found no link between LRRK2 mutations and LBD, we found a LRRK2 mutation associated with LBD that might be restricted to patients with North African ancestors. Our study illustrates the need to introduce ethnic diversity as stratifying factor in the analysis of genetic causes of neurodegenerative disorders. The current development of disease-modifying drugs modulating LRRK2 kinase activity could justify to screen North-African patients with LBD for the G2019S LRRK2 mutation.Article: The G2019S mutation of Leucine-Rich Repeat Kinase 2 is a cause of Lewy Body Dementia in patients with North African ancestors. Segers K, Benoit F, Levy S, Martinet V, Schulz JG, Bertrand F, De Bourgoing G, Tatillo C, Praet JP, Vandernoot I, Desmyter L, Peyrassol X, Kehagias P, Smits G, Dumoulin B, Besse-Hammer T, Dachy B, Surquin M. Alzheimer’s Disease and Associated Disorders (in press).

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