Family History is Associated with Phenotype in Dementia with Lewy Bodies

Vergouw, Leonie J.M.; Bosman, Brechje; Beek, Marleen van de; Salomé, Mariet; Hoogers, Susanne E; Steenoven, Inger van; Roks, Gerwin; Bonifati, Vincenzo; Swieten, John C. van; Lemstra, Afina W.; Jong, Frank Jan de

doi:10.3233/jad-190825

Cited by 2 publications

(4 citation statements)

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“…In agreement with our data, previous studies have reported a median survival in DLB ranging from 2 to 7 years [23,24]. Clinical subtypes did not appear to influence survival in our study, in contrast to the literature, where inaugural visual hallucinations were correlated with shorter survival and parkinsonism was rather associated with a longer survival [24][25][26][27]. Indeed, Jellinger et al showed that the presence of parkinsonism as the initial symptom in Lewy body dementia (LBD), which encompasses both DLB and Parkinson's disease with dementia (PDD), can have a significant impact on mortality and is associated with a longer survival rate.…”

Section: Discussionsupporting

confidence: 93%

“…Finally, the median survival of DLB our study was 6 years. In agreement with our data, previous studies have reported a median survival in DLB ranging from 2 to 7 years [23,24]. Clinical subtypes did not appear to influence survival in our study, in contrast to the literature, where inaugural visual hallucinations were correlated with shorter survival and parkinsonism was rather associated with a longer survival [24][25][26][27].…”

Section: Discussionsupporting

confidence: 89%

“…Moreover, in accordance with previous studies, median survival was significantly shorter for males. As far as genetic factors are concerned, the APOE 4 allele carrying-status, which has been formerly described as a factor of short survival in DLB, did not influence survival in our cohort [24][25][26][27].…”

Section: Discussionmentioning

confidence: 43%

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Subtypes of Dementia with Lewy Bodies: Clinical Features, Survival, and Apolipoprotein E Effect

Gharbi,

Nasri,

Sghaier

et al. 2023

Journal of Alzheimer's Disease Reports

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Background: Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disease with various clinical symptoms. Limited data have described the clinical subtypes of DLB. Objective: We aimed to compare clinical subtypes of DLB according to initial symptoms and to study the effect of Apolipoprotein E (APOE) gene in DLB. Methods: We included DLB patients classified into three groups based on initial symptoms: non-motor onset (cognitive and/or psychiatric) (NMO-DLB), motor onset (parkinsonism and/or gait disorders) (MO-DLB), and mixed onset (non-motor and motor symptoms) (MXO-DLB). Clinical and APOE genotype associations and survival were analyzed. Results: A total of 268 patients were included (NMO-DLB = 75%, MXO-DLB = 15.3%, MO-DLB = 9.7%). Visual hallucinations were more frequent (p = 0.025), and attention was less commonly impaired in MXO-DLB (p = 0.047). When adjusting with APOE ɛ4 status (APOE genotype performed in 155 patients), earlier falls and frontal lobe syndrome were more common in MXO-DLB (p = 0.044 and p = 0.023, respectively). The median MMSE decline was 2.1 points/year and the median FAB decline was 1.9 points/year, with no effect of clinical subtypes. Median survival was 6 years. It was similar in DLB subtypes (p = 0.62), but shorter for patients with memory symptoms at onset (p = 0.04) and for males (p = 0.0058). Conclusions: Our study revealed a few differences between DLB clinical subtypes. APOE ɛ4 appears to be associated with earlier falls and a higher prevalence of frontal syndrome in MXO-DLB. However, DLB clinical subtypes did not impact on survival. Nevertheless, survival analysis identified other poor prognosis factors, notably inaugural memory impairment and male gender.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 89%

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Subtypes of Dementia with Lewy Bodies: Clinical Features, Survival, and Apolipoprotein E Effect

Gharbi,

Nasri,

Sghaier

et al. 2023

Journal of Alzheimer's Disease Reports

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“…2 A number of people affected by dementia have been increasing rapidly, and it is predicted that, for every 3 s, a new case of dementia has been reported worldwide. Various factors such as age, 3 family history, 4 and heredity 5 account for the development of AD. Among these, age is the greatest risk factor for AD as the prevalence of the disease increases with the increasing age.…”

Section: Introductionmentioning

confidence: 99%

How Does the Mono-Triazole Derivative Modulate Aβ₄₂ Aggregation and Disrupt a Protofibril Structure: Insights from Molecular Dynamics Simulations

Kaur

Goyal

et al. 2020

ACS Omega

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Clinical studies have identified that abnormal selfassembly of amyloid-β (Aβ) peptide into toxic fibrillar aggregates is associated with the pathology of Alzheimer's disease (AD). The most acceptable therapeutic approach to stop the progression of AD is to inhibit the formation of β-sheet-rich structures. Recently, we designed and evaluated a series of novel mono-triazole derivatives 4(a−x), where compound 4v was identified as the most potent inhibitor of Aβ 42 aggregation and disaggregates preformed Aβ 42 fibrils significantly. Moreover, 4v strongly averts the Cu 2+ -induced Aβ 42 aggregation and disaggregates the preformed Cu 2+ -induced Aβ 42 fibrils, halts the generation of reactive oxygen species, and shows neuroprotective effects in SH-SY5Y cells. However, the underlying molecular mechanism of inhibition of Aβ 42 aggregation by 4v and disaggregation of preformed Aβ 42 fibrils remains obscure. In this work, molecular dynamics (MD) simulations have been performed to explore the conformational ensemble of the Aβ 42 monomer and a pentameric protofibril structure of Aβ 42 in the presence of 4v. The MD simulations highlighted that 4v binds preferentially at the central hydrophobic core region of the Aβ 42 monomer and chains D and E of the Aβ 42 protofibril. The dictionary of secondary structure of proteins analysis indicated that 4v retards the conformational conversion of the helix-rich structure of the Aβ 42 monomer into the aggregation-prone β-sheet conformation. The binding free energy calculated by the molecular mechanics Poisson− Boltzmann surface area method revealed an energetically favorable process with ΔG binding = −44.9 ± 3.3 kcal/mol for the Aβ 42 monomer−4v complex. The free energy landscape analysis highlighted that the Aβ 42 monomer−4v complex sampled conformations with significantly higher helical contents (35 and 49%) as compared to the Aβ 42 monomer alone (17%). Compound 4v displayed hydrogen bonding with Gly37 (chain E) and π−π interactions with Phe19 (chain D) of the Aβ 42 protofibril. Further, the per-residue binding free energy analysis also highlighted that Phe19 (chain D) and Gly37 (chain E) of the Aβ 42 protofibril showed the maximum contribution in the binding free energy. The decreased binding affinity and residue−residue contacts between chains D and E of the Aβ 42 protofibril in the presence of 4v indicate destabilization of the Aβ 42 protofibril structure. Overall, the structural information obtained through MD simulations indicated that 4v stabilizes the native helical conformation of the Aβ 42 monomer and persuades a destabilization in the protofibril structure of Aβ 42 . The results of the study will be useful in the rational design of potent inhibitors against amyloid aggregation.

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Family History is Associated with Phenotype in Dementia with Lewy Bodies

Cited by 2 publications

References 29 publications

Subtypes of Dementia with Lewy Bodies: Clinical Features, Survival, and Apolipoprotein E Effect

Subtypes of Dementia with Lewy Bodies: Clinical Features, Survival, and Apolipoprotein E Effect

How Does the Mono-Triazole Derivative Modulate Aβ₄₂ Aggregation and Disrupt a Protofibril Structure: Insights from Molecular Dynamics Simulations

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Family History is Associated with Phenotype in Dementia with Lewy Bodies

Cited by 2 publications

References 29 publications

Subtypes of Dementia with Lewy Bodies: Clinical Features, Survival, and Apolipoprotein E Effect

Subtypes of Dementia with Lewy Bodies: Clinical Features, Survival, and Apolipoprotein E Effect

How Does the Mono-Triazole Derivative Modulate Aβ42 Aggregation and Disrupt a Protofibril Structure: Insights from Molecular Dynamics Simulations

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Product

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How Does the Mono-Triazole Derivative Modulate Aβ₄₂ Aggregation and Disrupt a Protofibril Structure: Insights from Molecular Dynamics Simulations