Parsing heterogeneity within dementia with Lewy bodies using clustering of biological, clinical, and demographic data

Dementia with Lewy bodies (DLB) includes various core clinical features that result in different phenotypes. In addition, Alzheimer's disease (AD) and cerebrovascular pathologies are common in DLB. All this increases the heterogeneity within DLB and hampers clinical diagnosis. We addressed this heterogeneity by investigating subgroups of patients with similar biological, clinical, and demographic features. We studied 107 extensively phenotyped DLB patients from the European DLB consortium. Factorial analysis of mixed data (FAMD) was used to identify dimensions in the data, based on sex, age, years of education, disease duration, Mini-Mental State Examination (MMSE), cerebrospinal fluid (CSF) levels of AD biomarkers, core features of DLB, and regional brain atrophy. Subsequently, hierarchical clustering analysis was used to subgroup individuals based on the FAMD dimensions. We identified 3 dimensions using FAMD that explained 38% of the variance. Subsequent hierarchical clustering identified 4 clusters. Cluster 1 was characterized by amyloid-β and cerebrovascular pathologies, medial temporal atrophy, and cognitive fluctuations. Cluster 2 had posterior atrophy and showed the lowest frequency of visual hallucinations and cognitive fluctuations and the worst cognitive performance. Cluster 3 had the highest frequency of tau pathology, showed posterior atrophy, and had a low frequency of parkinsonism. Cluster 4 had virtually normal AD biomarkers, the least regional brain atrophy and cerebrovascular pathology, and the highest MMSE scores. This study demonstrates that there are subgroups of DLB patients with different biological, clinical, and demographic characteristics. These findings may have implications in the diagnosis and prognosis of DLB, as well as in the treatment response in clinical trials. The online version contains supplementary material available at 10.1186/s13195-021-00946-w

Function of CBP and CBP dependant acetylations in epigenetic regulation of the spatial memory formation : study in pathologic models and therapeutic implications for Alzheimer’s disease

La maladie d’Alzheimer est une maladie neurodégénérative liée à l’âge qui se caractérise par des troubles progressifs de la mémoire et entraîne notamment une atteinte de la mémoire à long terme. Cette dernière se met en place grâce à des mécanismes dépendants de l’hippocampe dorsale. Ces processus de consolidation dépendent d’une activation transcriptionnelle et d’une synthèse de nouvelles protéines. Il est maintenant bien établi que les régulations transcriptionnelles des gènes reposent sur un état de “compétence” de la chromatine, lui-même dicté par le code épigénétique. La transcription dépendante d’une histone acétyltransférase (HAT), la CREB-Binding Protein (CBP) et des acétylations des histones, semble impliquée dans ces mécanismes de mémorisation. Nous étudions les régulations de CBP et d’autres HAT, ainsi que l’état des acétylations des histones dans l’hippocampe de rats ayant suivi un apprentissage spatial en piscine de Morris, et nous essayons de décrypter comment ces modifications sont altérées dans des modèles in vivo de rat ayant subi des lésions et montrant des déficiences cognitives similaires à celles retrouvées dans la maladie d’Alzheimer. Ensuite, nous avons cherché à déterminer in vitro l’implication de la voie glutamatergique sur la dynamique d’acétylation des histones. Notre but est de comprendre si et comment une stratégie basée sur l’utilisation de molécules capables de moduler les acétylations (i.e. activateurs de HAT) peut être efficace pour contrer/retarder les pertes cognitives qui ont un effet dévastateur sur la qualité de vie de ces patients.Alzheimer disease (AD) is an age-related neurodegenerative disease, which involves progressive cognition impairment and notably long term memory damages. This one takes place thanks to dorsal hippocampus dependant mechanisms. These consolidation processes depend on transcriptional activation and de novo proteins synthesis. It is now well established that genes transcriptional regulations rest on a chromatin ability, itself dictated by epigenetic code. Transcription pathways dependant of one HAT, the CREB-Binding Protein (CBP) and histone acetylations, seems to be involved in these memory mechanisms. We study CBP and other HAT regulations, thus the histone acetylations statement in rat hippocampus having undergone a spatial learning in Morris Water Maze and we try to decipher how these modifications are impaired in in vivo rat models having undergone lesions and exhibiting cognitive deficiencies similar of those found in Alzheimer’s disease. Likewise, we have tried to determine in vitro glutamatergic pathway implication upon the histone acetylation dynamic. Our aim is to understand whether and how a strategy based on the use of molecules able to modulate acetylations (i.e. HAT activator) can be effective for counter/delay cognitive impairment which have a devastating effect upon the quality of life of these patients

Function of CBP and CBP dependant acetylations in epigenetic regulation of the spatial memory formation,tudy in pathologic models and therapeutic implications for Alzheimer s disease

La maladie d'Alzheimer est une maladie neurodégénérative liée à l'âge qui se caractérise par des troubles progressifs de la mémoire et entraîne notamment une atteinte de la mémoire à long terme. Cette dernière se met en place grâce à des mécanismes dépendants de l'hippocampe dorsale. Ces processus de consolidation dépendent d'une activation transcriptionnelle et d'une synthèse de nouvelles protéines. Il est maintenant bien établi que les régulations transcriptionnelles des gènes reposent sur un état de compétence de la chromatine, lui-même dicté par le code épigénétique. La transcription dépendante d'une histone acétyltransférase (HAT), la CREB-Binding Protein (CBP) et des acétylations des histones, semble impliquée dans ces mécanismes de mémorisation. Nous étudions les régulations de CBP et d'autre apprentissage spatial en piscine de Morris, et nous essayons de décrypter comment ces modifications sont altérées dans des modèles in vivo de rat ayant subi des lésions et montrant des déficiences cognitives similaires à celles retrouvées dans la maladie d'Alzheimer. Ensuite, nous avons cherché à déterminer in vitro l'implication de la voie glutamatergique sur la dynamique d'acétylation des histones. Notre but est de comprendre si et comment une stratégie basée sur l'utilisation de molécules capables de moduler les acétylations (i.e. activateurs de HAT) peut être efficace pour contrer/retarder les pertes cognitives qui ont un effet dévastateur sur la qualité de vie de ces patients.Alzheimer disease (AD) is an age-related neurodegenerative disease, which involves progressive cognition impairment and notably long term memory damages. This one takes place thanks to dorsal hippocampus dependant mechanisms. These consolidation processes depend on transcriptional activation and de novo proteins synthesis. It is now well established that genes transcriptional regulations rest on a chromatin ability, itself dictated by epigenetic code. Transcription pathways dependant of one HAT, the CREB-Binding Protein (CBP) and histone acetylations, seems to be involved in these memory mechanisms. We study CBP and other HAT regulations, thus the histone acetylations statement in rat hippocampus having undergone a spatial learning in Morris Water Maze and we try to decipher how these modifications are impaired in in vivo rat models having undergone lesions and exhibiting cognitive deficiencies similar of those found in Alzheimer s disease. Likewise, we have tried to determine in vitro glutamatergic pathway implication upon the histone acetylation dynamic. Our aim is to understand whether and how a strategy based on the use of molecules able to modulate acetylations (i.e. HAT activator) can be effective for counter/delay cognitive impairment which have a devastating effect upon the quality of life of these patients

Diagnostic value of cerebro-spinal fluid biomarkers in dementia with lewy bodies

Dementia with Lewy Bodies (DLB) is the second most common form of dementia after Alzheimer's disease (AD), accounting for 15% to 20% of neuropathologically defined cases. Two-thirds of the patients affected are not or misdiagnosed because of the clinical similarity of these two pathologies. In this review, we evaluate the discriminatory power of cerebrospinal fluid (CSF) biomarkers by focusing more specifically on differential diagnosis between DLB and AD. We focus on the AD biological biomarkers used in clinical routine as well as the biomarkers under study and more particularly the alpha-synuclein assay. Thus, among the AD biomarkers (t-Tau, phospho-Tau181, Aβ42 and Aβ40) used routinely, t-Tau and phospho-Tau181 have shown excellent discrimination whatever the clinical stages severity. Aβ42 level is pathological in DLB patients at the demented stage, but is almost not impacted at the prodromal stage. Alpha-synuclein assay in the CSF has also an interest in the discrimination between DLB and AD but not in segregation between DLB and healthy elderly subjects. Thus, globally the biological diagnosis on CSF basis makes it possible, to separate the DLBs from the ADs. In addition, the development of biomarkers such as phospho-alpha-synuclein and oligomeric alpha-synuclein should help to reinforce this discrimination power

Modulateurs épigénétiques des acétylations comme nouvelles voies thérapeutiques dans les pathologies de la mémoire telle que la maladie d' Alzheimer

STRASBOURG ILLKIRCH-Pharmacie (672182101) / SudocSudocFranceF

Rôle de CBP et des acétylations dépendantes de CBP dans les régulations épigénétiques de la formation de la mémoire spatiale (Etude dans des modèles pathologiques et implications thérapeutiques pour la maladie d Alzheimer)

La maladie d Alzheimer est une maladie neurodégénérative liée à l âge qui se caractérise par des troubles progressifs de la mémoire et entraîne notamment une atteinte de la mémoire à long terme. Cette dernière se met en place grâce à des mécanismes dépendants de l hippocampe dorsale. Ces processus de consolidation dépendent d une activation transcriptionnelle et d une synthèse de nouvelles protéines. Il est maintenant bien établi que les régulations transcriptionnelles des gènes reposent sur un état de compétence de la chromatine, lui-même dicté par le code épigénétique. La transcription dépendante d une histone acétyltransférase (HAT), la CREB-Binding Protein (CBP) et des acétylations des histones, semble impliquée dans ces mécanismes de mémorisation. Nous étudions les régulations de CBP et d autre apprentissage spatial en piscine de Morris, et nous essayons de décrypter comment ces modifications sont altérées dans des modèles in vivo de rat ayant subi des lésions et montrant des déficiences cognitives similaires à celles retrouvées dans la maladie d Alzheimer. Ensuite, nous avons cherché à déterminer in vitro l implication de la voie glutamatergique sur la dynamique d acétylation des histones. Notre but est de comprendre si et comment une stratégie basée sur l utilisation de molécules capables de moduler les acétylations (i.e. activateurs de HAT) peut être efficace pour contrer/retarder les pertes cognitives qui ont un effet dévastateur sur la qualité de vie de ces patients.Alzheimer disease (AD) is an age-related neurodegenerative disease, which involves progressive cognition impairment and notably long term memory damages. This one takes place thanks to dorsal hippocampus dependant mechanisms. These consolidation processes depend on transcriptional activation and de novo proteins synthesis. It is now well established that genes transcriptional regulations rest on a chromatin ability, itself dictated by epigenetic code. Transcription pathways dependant of one HAT, the CREB-Binding Protein (CBP) and histone acetylations, seems to be involved in these memory mechanisms. We study CBP and other HAT regulations, thus the histone acetylations statement in rat hippocampus having undergone a spatial learning in Morris Water Maze and we try to decipher how these modifications are impaired in in vivo rat models having undergone lesions and exhibiting cognitive deficiencies similar of those found in Alzheimer s disease. Likewise, we have tried to determine in vitro glutamatergic pathway implication upon the histone acetylation dynamic. Our aim is to understand whether and how a strategy based on the use of molecules able to modulate acetylations (i.e. HAT activator) can be effective for counter/delay cognitive impairment which have a devastating effect upon the quality of life of these patients.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

CSF in Epileptic Prodromal Alzheimer's Disease: No Diagnostic Contribution but a Pathophysiological One

International audienceObjective: To study whether cerebrospinal fluid (CSF) analysis may serve as a diagnostic test for the screening of epilepsy in sporadic prodromal Alzheimer's disease (AD). Methods: A total of 29 patients with epileptic prodromal sporadic AD patients (epADs) were included and were retrospectively compared with 38 non-epileptic prodromal AD patients (nepADs) for demographics, clinical features, Mini-Mental Status Examination (MMSE) results, CSF biomarkers, and electro-radiological features. Results: Our study did not show any significant differences in CSF biomarkers regarding neurodegeneration, albumin levels, and inflammation between epADs and nepADs. The epADs were significantly older at diagnosis (p = 0.001), more hypertensive (p = 0.01), and displayed larger white matter hyperintensities on brain magnetic resonance imaging (MRI; p = 0.05). There was a significant correlation between the CSF Aβ-42 and Aβ-40 levels with interictal epileptiform discharges and delta slowing on EEGs recordings, respectively (p = 0.03). Conclusions: Our study suggests that CSF may not serve as a surrogate marker of epilepsy in prodromal AD and cannot circumvent the operator-dependent and time-consuming interpretation of EEG recordings. In humans, AD-related epileptogenesis appears to involve the Aβ peptides but likely also additional non-amyloid factors such as small-vessel disease (i.e., white matter hyperintensities)