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

GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study

Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10). One additional genetic locus previously linked to psychosis in Alzheimer's disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10. We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders

Age-Related Memory Impairment Is Associated with Disrupted Multivariate Epigenetic Coordination in the Hippocampus

Mounting evidence linking epigenetic regulation to memory-related synaptic plasticity raises the possibility that altered chromatin modification dynamics might contribute to age-dependent cognitive decline. Here we show that the coordinated orchestration of both baseline and experience-dependent epigenetic regulation seen in the young adult hippocampus is lost in association with cognitive aging. Using a well-characterized rat model that reliably distinguishes aged individuals with significant memory impairment from others with normal memory, no single epigenetic mark or experience-dependent modification in the hippocampus uniquely predicted differences in the cognitive outcome of aging. The results instead point to a multivariate pattern in which modification-specific, bidirectional chromatin regulation is dependent on recent behavioral experience, chronological age, cognitive status, and hippocampal region. Whereas many epigenetic signatures were coupled with memory capacity among young adults and aged rats with preserved cognitive function, such associations were absent among aged rats with deficits in hippocampal memory. By comparison with the emphasis in current preclinical translational research on promoting chromatin modifications permissive for gene expression, our findings suggest that optimally successful hippocampal aging may hinge instead on enabling coordinated control across the epigenetic landscape

Clinical reporting following the quantification of cerebrospinal fluid biomarkers in Alzheimer's disease: An international overview

Introduction: The current practice of quantifying cerebrospinal fluid (CSF) biomarkers as an aid in the diagnosis of Alzheimer's disease (AD) varies from center to center. For a same biochemical profile, interpretation and reporting of results may differ, which can lead to misunderstandings and raises questions about the commutability of tests. Methods: We obtained a description of (pre-)analytical protocols and sample reports from 40 centers worldwide. A consensus approach allowed us to propose harmonized comments corresponding to the different CSF biomarker profiles observed in patients. Results: The (pre-)analytical procedures were similar between centers. There was considerable heterogeneity in cutoff definitions and report comments. We therefore identified and selected by consensus the most accurate and informative comments regarding the interpretation of CSF biomarkers in the context of AD diagnosis. Discussion: This is the first time that harmonized reports are proposed across worldwide specialized laboratories involved in the biochemical diagnosis of AD

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