Combined Alzheimer's disease and cerebrovascular staging explains advanced dementia cognition

Zea‐Sevilla, María Ascensión; Fernández-Blázquez, Miguel A.; Calero, Miguel; Bermejo-Velasco, Pedro; Rábano, Alberto

doi:10.1016/j.jalz.2015.01.004

Cited by 18 publications

(14 citation statements)

References 47 publications

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“…Clinical features are listed in the Table. Procedures for brain tissue extraction, processing, and neuropathological classification had been published before. 28,29 Postmortem brain tissue was obtained from donors through a rapid neuropathological autopsy (mean postmortem interval = 5.5 hours). After brain removal, two symmetric brain halves were obtained through a midsagittal incision and the right hemibrain was flash-frozen by immersion in -60 C isopentane.…”

Section: Methodsmentioning

confidence: 99%

Seeding variability of different alpha synuclein strains in synucleinopathies

Candelise

Schmitz

Llorens

et al. 2019

Annals of Neurology

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Objectives: Currently, the exact reasons why different α-synucleinopathies exhibit variable pathologies and phenotypes are still unknown. A potential explanation may be the existence of distinctive α-synuclein conformers or strains. Here, we intend to analyze the seeding activity of dementia with Lewy bodies (DLB) and Parkinson's disease (PD) brain-derived α-synuclein seeds by real-time quaking-induced conversion (RT-QuIC) and to investigate the structure and morphology of the α-synuclein aggregates generated by RT-QuIC. Methods: A misfolded α-synuclein-enriched brain fraction from frontal cortex and substantia nigra pars compacta tissue, isolated by several filtration and centrifugation steps, was subjected to α-synuclein/RT-QuIC analysis. Our study included neuropathologically well-characterized cases with DLB, PD, and controls (Ctrl). Biochemical and morphological analyses of RT-QuIC products were conducted by western blot, dot blot analysis, Raman spectroscopy, atomic force microscopy, and transmission electron microscopy. Results: Independently from the brain region, we observed different seeding kinetics of α-synuclein in the RT-QuIC in patients with DLB compared to PD and Ctrl. Biochemical characterization of the RT-QuIC product indicated the generation of a proteinase K-resistant and fibrillary α-synuclein species in DLB-seeded reactions, whereas PD and control seeds failed in the conversion of wild-type α-synuclein substrate. Interpretation: Structural variances of α-synuclein seeding kinetics and products in DLB and PD indicated, for the first time, the existence of different α-synuclein strains in these groups. Therefore, our study contributes to a better understanding of the clinical heterogeneity among α-synucleinopathies, offers an opportunity for a specific diagnosis, and opens new avenues for the future development of strain-specific therapies. ANN NEUROL 2019;85:691-703 S ynucleinopathies, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB), are a class of neurodegenerative diseases characterized by the presence of insoluble intraneural deposits consisting of fibrillary α-synuclein, 1,2 referred to as Lewy bodies. A PD with dementia (PDD) diagnosis is appropriate when the cognitive symptoms View this article online at wileyonlinelibrary.com.

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Section: Methodsmentioning

confidence: 99%

Seeding variability of different alpha synuclein strains in synucleinopathies

Candelise

Schmitz

Llorens

et al. 2019

Annals of Neurology

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“…Furthermore, epidemiological studies have increasingly demonstrated that traditional vascular risk factors, such as obesity, diabetes and hypertension, have important etiological roles not only in vascular dementia but also in AD [7–9]. Due to the increased recognition of a significant overlap between these conditions, there is a need to examine vascular dementia and AD beyond a simple dichotomy, but as part of a continuous spectrum of age-related dementia where factors contributing to either vascular dementia or AD are considered together [15]. …”

Section: Vascular Dementia and Alzheimer’s Disease: Age-related Demenmentioning

confidence: 99%

Adipocyte-derived factors in age-related dementia and their contribution to vascular and Alzheimer pathology

Ishii

Iadecola

2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Age-related dementia is increasingly recognized as having a mixed pathology, with contributions from both cerebrovascular factors and pathogenic factors associated with Alzheimer’s disease (AD). Furthermore, there is accumulating evidence that vascular risk factors in midlife, e.g., obesity, diabetes, and hypertension, increase the risk of developing late-life dementia. Since obesity and changes in body weight/adiposity often drive diabetes and hypertension, understanding the relationship between adiposity and age-related dementia may reveal common underlying mechanisms. Here we offer a brief appraisal of how changes in body weight and adiposity are related to both AD and dementia on vascular basis, and examine the involvement of two key adipocyte-derived hormones: leptin and adiponectin. The evidence suggests that in midlife increased body weight/adiposity and subsequent changes in adipocyte-derived hormones may increase the long-term susceptibility to dementia. On the other hand, later in life, decreases in body weight/adiposity and related hormonal changes are early manifestations of disease that precede the onset of dementia and may promote AD and vascular pathology. Understanding the contribution of adiposity to age-related dementia may help identify the underlying pathological mechanisms common to both vascular dementia and AD, and provide new putative targets for early diagnosis and therapy.

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“…These patients can be closely studied within the center's facilities offering valuable information on their disease progress and ways to maximize management. The foundation's research has shown that lower cardiac hemodynamic performance is significantly associated with structural brain damage that parallels diminished executive function and other cognitive brain abnormalities [74]. A large brain bank facility is the source of multiple neuropathological research studies.…”

Section: Preventive Alzheimer's Clinicsmentioning

confidence: 99%

Alzheimer’s Turning Point

Torre

2016

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Combined Alzheimer's disease and cerebrovascular staging explains advanced dementia cognition

Abstract: The combination of scales measuring cerebral vascular and Alzheimer's type pathology allowed a classification of patients that reveals differences between groups in premortem cognitive features.

Cited by 18 publications

References 47 publications

Seeding variability of different alpha synuclein strains in synucleinopathies

Seeding variability of different alpha synuclein strains in synucleinopathies

Adipocyte-derived factors in age-related dementia and their contribution to vascular and Alzheimer pathology

Alzheimer’s Turning Point

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