Cardiovascular Risk Factors Promote Brain Hypoperfusion Leading to Cognitive Decline and Dementia

Torre, Jack C. de la

doi:10.1155/2012/367516

Cited by 346 publications

(261 citation statements)

References 165 publications

(180 reference statements)

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“…14 As a result of cerebral hypoperfusion, brain atrophy may occur. 15,16 Experimental evidence from animal models indeed suggests that cerebral hypoperfusion leads to cerebral microvascular damage, neuropathologic processes, and cognitive dysfunction, supporting the concept that cerebral hypoperfusion causes neurodegeneration. 17,18 Yet, the majority of studies in human subjects linking CBF to brain atrophy had a cross-sectional design, precluding unraveling cause and effect in the association.…”

Section: Introductionmentioning

confidence: 94%

The Bidirectional Association between Reduced Cerebral Blood Flow and Brain Atrophy in the General Population

Zonneveld

Loehrer

Hofman

et al. 2015

J Cereb Blood Flow Metab

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The question remains whether reduced cerebral blood flow (CBF) leads to brain atrophy or vice versa. We studied the longitudinal relation between CBF and brain volume in a community-dwelling population. In the Rotterdam Study, 3011 participants (mean age 59.6 years (s.d. 8.0)) underwent repeat brain magnetic resonance imaging to quantify brain volume and CBF at two time points. Adjusted linear regression models were used to investigate the bidirectional relation between CBF and brain volume. We found that smaller brain volume at baseline was associated with a steeper decrease in CBF in the whole population (standardized change per s.d. increase of total brain volume (TBV) = 0.296 (95% confidence interval (CI) 0.200; 0.393)). Only in persons aged ⩾ 65 years, a lower CBF at baseline was associated with steeper decline of TBV (standardized change per s.d. increase of CBF = 0.003 (95% CI − 0.004; 0.010) in the whole population and 0.020 (95% CI 0.004; 0.036) in those aged ⩾ 65 years of age). Our results indicate that brain atrophy causes CBF to decrease over time, rather than vice versa. Only in persons aged 465 years of age did we find lower CBF to also relate to brain atrophy.

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Section: Introductionmentioning

confidence: 94%

The Bidirectional Association between Reduced Cerebral Blood Flow and Brain Atrophy in the General Population

Zonneveld

Loehrer

Hofman

et al. 2015

J Cereb Blood Flow Metab

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“…Hypertension, diabetic dyslipidemia and atrial fibrillation are associated with cerebral hypoperfusion, and accelerated cognitive decline through complex, and poorly understood mechanisms [15]. Since the 5-HT2A receptor is expressed on smooth muscle cells in the gut, heart and vasculature where it mediates 5-HTinduced-contraction [16] and -vasoconstriction [17], we next Figure 6: Heating (65 deg C x 30 mins) caused gain in N2A neurotoxicity in a subset of six diabetic patients with co-morbid PD (n=5) or dementia (n=1) (A).…”

Section: Effect Of Diabetic Pd Autoantibodies In Mouse Hl1 Atrial Carmentioning

confidence: 99%

Circulating Neurotoxic 5-HT2A Receptor Agonist Autoantibodies in Adult Type 2 Diabetes with Parkinson’s Disease

Zimering¹

2018

JED

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Aims: To test whether circulating neurotoxic autoantibodies increase in adult type 2 diabetes mellitus with Parkinson's disease (PD) or dementia. To identify the G-protein coupled receptor on neuroblastoma cells mediating neural inhibitory effects in diabetic Parkinson's disease plasma autoantibodies. To determine the mechanism of accelerated neuroblastoma cell death and acute neurite retraction induced by diabetic Parkinson's disease and dementia autoantibodies.Methods: Protein-A eluates from plasma of twelve older adult male diabetic patients having Parkinson's disease (n=10) or dementia (n=2), and eight age-matched control diabetic patients were tested for ability to cause accelerated N2A neuroblastoma cell death and acute neurite retraction. Specific antagonists of G protein coupled receptors belonging to the G alpha q subfamily of heterotrimetric G-proteins, the phospholipase C/inositol triphosphate/Ca2+ pathway, or the RhoA/Rho kinase pathway were tested for ability to block diabetic Parkinson's disease/dementia autoantibodyinduced neurite retraction or N2A accelerated cell loss. Sequential Liposorber LA-15 dextran sulfate cellulose/protein-A affinity chromatography was used to obtain highly-purified fractions of diabetic Parkinson's disease autoantibodies .Results: Mean accelerated neuroblastoma cell loss induced by diabetic Parkinson's disease or dementia autoantibodies significantly exceeded (P = 0.001) the level of N2A cell loss induced by an identical concentration of the diabetic autoantibodies in control patients without these two comorbid neurodegenerative disorders. Co-incubation of diabetic Parkinson's disease and dementia autoantibodies with two-hundred nanomolar concentrations of M100907, a highly selective 5-HT2AR antagonist, completely prevented autoantibody-induced accelerated N2A cell loss and neurite retraction. A higher concentration (500 nM-10μM) of alpha-1 adrenergic, angiotensin II type 1, or endothelin A receptor antagonists did not substantially inhibit autoantibody-induced neuroblastoma cell death or prevent neurite retraction. Antagonists of the inositol triphosphate receptor (2-APB, 50μM), the intracellular calcium chelator (BAPTA-AM, 30 μM) and Y27632 (10 μM), a selective RhoA/Rho kinase inhibitor, each completely blocked acute neurite retraction induced by sixty nanomolar concentrations of diabetic Parkinson's disease autoantibodies. Co-incubation with 2-APB (1-2 μM) for 8 hours' prevented autoantibody-induced N2A cell loss. The highly-purified fraction obtained after Liposorber LA/protein-A affinity chromatography in hypertriglyceridemic diabetic dementia and Parkinson's disease plasmas had apparent MWs > 30 kD, and displayed enhanced N2A toxicity requiring substantially higher concentrations of 5-HT2AR antagonists (M100907, ketanserin, spiperone) to effectively neutralize. Conclusion:These data suggest increased autoantibodies in older adult diabetes with Parkinson's disease or dementia cause accelerated neuron loss via the 5-hydroxytryptamine 2 receptor coupled to ino...

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“…Possible explanations include microinfarcts, invisible to magnetic resonance techniques, or neuronal damage through other mechanisms such as breakdown in the blood-brain barrier, chronic hypoperfusion, hypoxia, inflammation, and oxidative stress. [21][22][23][24][25] While hypothetical, these possible pathways require investigation because they might represent therapeutic targets.…”

mentioning

confidence: 99%

Vascular risk and Aβ interact to reduce cortical thickness in AD vulnerable brain regions

et al. 2014

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Objective: The objective of this study was to define whether vascular risk factors interact with b-amyloid (Ab) in producing changes in brain structure that could underlie the increased risk of Alzheimer disease (AD).Methods: Sixty-six cognitively normal and mildly impaired older individuals with a wide range of vascular risk factors were included in this study. The presence of Ab was assessed using [11 C] Pittsburgh compound B-PET imaging, and cortical thickness was measured using 3-tesla MRI. Vascular risk was measured with the Framingham Coronary Risk Profile Index.Results: Individuals with high levels of vascular risk factors have thinner frontotemporal cortex independent of Ab. These frontotemporal regions are also affected in individuals with Ab deposition, but the latter show additional thinning in parietal cortices. Ab and vascular risk were found to interact in posterior (especially in parietal) brain regions, where Ab has its greatest effect. In this way, the negative effect of Ab in posterior regions is increased by the presence of vascular risk. The prevalence of b-amyloid (Ab), the hallmark of Alzheimer disease (AD), is approximately 25% among cognitively normal elderly individuals, indicating that Ab alone might not be sufficient to drive brain changes and cognitive decline, and that other factors work with Ab to promote disease onset or progression. Vascular risk factors such as hypertension, dyslipidemia, and diabetes are known risk factors for dementia in persons with clinical syndromes suggesting AD pathology. Conclusion:1 One pathway by which vascular risk increases the likelihood of dementia is by causing vascular brain injury (VBI) (e.g., white matter lesions and infarcts). 1,2In vivo studies show that increased vascular risk is related to higher Ab burden. [3][4][5][6] Other work suggests that VBI per se is not associated with elevated Ab, and that the effects of VBI and Ab on brain structure and cognition are independent. 7,8 Together, these findings suggest that vascular risk factors may have independent effects on Ab and VBI, and therefore increase AD risk through multiple pathways.Integrity of the cerebral cortex is a major determinant of cognitive function. 9 A better understanding of the interplay between vascular risk and Ab pathology in relation to cortical thickness might yield insight into the factors that drive the development of AD. In this study, we assessed how Ab and vascular risk, alone and together, affect cerebral cortex, specifically evaluating

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Cardiovascular Risk Factors Promote Brain Hypoperfusion Leading to Cognitive Decline and Dementia

Cited by 346 publications

References 165 publications

The Bidirectional Association between Reduced Cerebral Blood Flow and Brain Atrophy in the General Population

The Bidirectional Association between Reduced Cerebral Blood Flow and Brain Atrophy in the General Population

Circulating Neurotoxic 5-HT2A Receptor Agonist Autoantibodies in Adult Type 2 Diabetes with Parkinson’s Disease

Vascular risk and Aβ interact to reduce cortical thickness in AD vulnerable brain regions

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