Cerebral small vessel disease and the risk of Alzheimer’s disease: A systematic review

Liu, Yue; Braidy, Nady; Poljak, Anne; Chan, Daniel K.; Sachdev, Perminder S.

doi:10.1016/j.arr.2018.06.002

Cited by 68 publications

(54 citation statements)

References 106 publications

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“…We have extended these earlier findings with a more comprehensive Proteomics examination of proteins in cerebral MVs, with an emphasis not only on individual mitochondrial structural proteins and energy producing proteins but also on proteins known to modulate mitochondrial numbers and function. We studied cerebral MVs because of recent recognition that this vascular segment is more susceptible to dysfunction during aging and disease than large arteries and that MVs are a primary initiation site for development of severe neurological diseases such cognitive impairment, vascular dementia, and AD (Liu et al, 2018;Bourassa et al, 2019;Erdő & Krajcsi 2019). Although several current findings confirmed results of our earlier studies, the expansive and thorough nature of the present study has yielded novel and surprising findings.…”

Section: Discussionsupporting

confidence: 79%

Sexual Differences in Mitochondrial Proteins in Rat Cerebral Microvessels: A Proteomic Approach

Chandra

Čikić

Harman

et al. 2019

Preprint

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Sex differences in mitochondrial numbers and function are present in large cerebral arteries, but it is unclear whether these differences extend to the microcirculation. We performed an assessment of mitochondria-related proteins in cerebral microvessels (MVs) isolated from young, male and female, Sprague-Dawley rats. MVs composed of arterioles, capillaries, and venules were isolated from the cerebrum and used to perform a 3 vs. 3 quantitative, multiplexed proteomics experiment utilizing tandem mass tags (TMT), coupled with liquid chromatography/mass spectrometry (LC/MS). MS data and bioinformatic analyses were performed using Proteome Discoverer version 2.2 and Ingenuity Pathway Analysis. We identified a total of 1,969 proteins, of which 1,871 were quantified by TMT labels. Sixty-four proteins were expressed significantly (p < 0.05) higher in female samples compared with male samples. Females expressed more mitochondrial proteins involved in energy production, mitochondrial membrane structure, anti-oxidant enzyme proteins, and those involved in fatty acid oxidation. Conversely, males had higher expression levels of mitochondria-destructive proteins. We validated our key Proteomics results with western blotting. Our findings reveal, for the first time, the full extent of sexual dimorphism in the mitochondrial metabolic protein profiles of MVs, which may contribute to sex-dependent cerebrovascular and neurological pathologies. SynopsisEnergy-producing proteins in the cerebral microvessels (MVs) of male and female rats were examined by quantitative discovery-based proteomics to gain insight into the sex-dependent etiology of cardiovascular and neurological diseases. Females expressed more mitochondrial proteins involved in energy production, membrane structure, anti-oxidant activity, and fatty acid oxidation. In contrast, males exhibited more mitochondria-destructive proteins such as mitochondrial eating protein. Our findings reveal for the first time the sexual dimorphism of mitochondria-related proteins in cerebral MVs, which may explain functional sex-related differences in MVs during health and in the etiology of neurological pathologies of cerebrovascular origin. ACKNOWLEDGMENTSWe thank Nancy Busija, MA, for editing the manuscript. We thank Dana Liu for technical help.

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Section: Discussionsupporting

confidence: 79%

Sexual Differences in Mitochondrial Proteins in Rat Cerebral Microvessels: A Proteomic Approach

Chandra

Čikić

Harman

et al. 2019

Preprint

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“…Therefore, damage and disease in the microvessels of the cerebrum cause the denaturation of blood vessels. These negative changes in the blood vessels destroy the function of the blood-brain barrier, thereby increasing the accumulation of β-amyloid due to increased permeability and protein runoff in the cerebral cortex [29][30][31][32][33].…”

Section: Discussionmentioning

confidence: 99%

Association between Pulse Pressure and Onset of Dementia in an Elderly Korean Population: A Cohort Study

Jung

Choi

Park

et al. 2020

IJERPH

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Objective: There is paucity of studies on the association between pulse pressure and the development of dementia, although this association has already been established. This study aimed at investigating the association between pulse pressure and the onset of dementia. Methods: We used the South Korean National Health Insurance Service claims cohort data to select 149,663 patients without dementia aged ≥60 years. We calculated adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for dementia using Cox proportional hazard models according to a pulse pressure classification (<50, 50-59, 60-69, 70-79, 80-89, or 90+). Results: Compared to women with pulse pressure <50, those with pulse pressures of 50-59, 60-69, and 90+ had higher HRs for dementia (1.14, 1.22, and 1.03, respectively). These associations were particularly strong in those on Medicaid insurance and from rural regions. However, there were no statistically significant results among men. Conclusions: A higher pulse pressure was associated with an elevated risk of dementia in women aged >60 years, particularly those on Medicaid and from rural regions, possibly due to their inability to access hypertension and other medical treatment. The establishment of dementia indicators will help to guide future health policies for the prevention of dementia.

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“…Indeed, BBB dysfunction may be a link across these disorders [94,95]. Notably, while Alzheimer's disease is traditionally considered a disease of neurofibrillary tangles and amyloid plaques, structural and functional changes in the microvessels may contribute directly to the pathogenesis of the disease [96][97][98][99][100], specifically disruption of brain clearance systems dependent on (water) transport across the BBB [29,101,102]. For a wide range of brain disorders, there is interest in interventions modulating brain hemodynamics and clearance system; neuromodulation may have powerful and unique actions (Principle 1).…”

Section: Discussionmentioning

confidence: 99%

Neurovascular-modulation

Khadka

Bikson²

2020

Preprint

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Neurovascular-modulation is based on two principles that derive directly from brain vascular ultra-structure, namely an exceptionally dense capillary bed (BBB length density: 972 mm/mm3) and a blood-brain-barrier (BBB) resistivity (ρ ~ 1×105 Ω.m) much higher than brain parenchyma/interstitial space (ρ ~ 4 Ω.m) or blood (ρ ~ 1 Ω.m). Principle 1: Electrical current crosses between the brain parenchyma (interstitial space) and vasculature, producing BBB electric fields (EBBB) that are > 400x of the average parenchyma electric field (ĒBRAIN), which in turn modulates transport across the BBB. Specifically, for a BBB space constant (λBBB) and wall thickness (dth-BBB): analytical solution for maximum BBB electric field (EABBB) is given as: (ĒBRAIN × λBBB) / dth-BBB. Direct vascular stimulation suggests novel therapeutic strategies such as boosting metabolic capacity or interstitial fluid clearance. Boosting metabolic capacity impacts all forms of neuromodulation, including those applying intensive stimulation or driving neuroplasticity. Boosting interstitial fluid clearance has broad implications as a treatment for neurodegenerative disease including Alzheimer’s disease. Principle 2: Electrical current in the brain parenchyma is distorted around brain vasculature, amplifying neuronal polarization. Specifically, vascular ultra-structure produces ~50% modulation of the average parenchyma electric field (ĒBRAIN) over the ~40 μm inter-capillary distance. The divergence of EBRAIN (activating function) is thus ~100 kV/m2 per unit average parenchyma electric field (ĒBRAIN). This impacts all forms of neuromodulation, including Deep Brain Stimulation (DBS), Spinal Cord Stimulation (SCS), Transcranial Magnetic Stimulation (TMS), Electroconvulsive Therapy (ECT), and transcranial electrical stimulation (tES) techniques such a transcranial Direct Current Stimulation (tDCS). Specifically, whereas spatial profile of EBRAIN along neurons is traditionally assumed to depend on macroscopic anatomy, it instead depends on local vascular ultra-structure.

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Cerebral small vessel disease and the risk of Alzheimer’s disease: A systematic review

Cited by 68 publications

References 106 publications

Sexual Differences in Mitochondrial Proteins in Rat Cerebral Microvessels: A Proteomic Approach

Sexual Differences in Mitochondrial Proteins in Rat Cerebral Microvessels: A Proteomic Approach

Association between Pulse Pressure and Onset of Dementia in an Elderly Korean Population: A Cohort Study

Neurovascular-modulation

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