Abstract P321: Is Amyloid Deposition in the Brain of Non-demented Older Adults a Consequence of High Blood Pressure and Arterial Stiffness?

Background: Advances in positron emission tomography imaging using amyloid specific ligands (e.g. PiB-PET) provide in vivo measurement of amyloid deposition in the brain, a hallmark of Alzheimer’s disease (AD) and dementia. Hypertension is believed to promote AD through arterial stiffening and cerebrovascular disease. We hypothesize that vascular measures are associated with amyloid in the brain. Methods: We studied 92 participants aged 83-96 in a follow-up of the Gingko Evaluation of Memory (GEM) Study with measures of: structural MRI of the brain; PiB-PET of brain amyloid deposition; resting blood pressure (BP), ankle brachial index (ABI) and mean arterial pressure (MAP); and vascular stiffness in the central (carotid-femoral ( cf PWV) and heart femoral ( hf PWV), peripheral (femoral-ankle ( fa PWV), and mixed (brachial-ankle ( ba PWV)) vascular beds, using a noninvasive and automated waveform analyzer (Colin Co., Komaki, Japan). Before study entry, all participants underwent ApoE-4 genotyping, detailed neuropsychological battery and adjudication of cognition by committee. Participants with a diagnosis of dementia were excluded from the sub-study. Results: Half (44/92) non-demented older adults in this sub-study were PiB+ for amyloid deposition in the brain. Amyloid deposition was associated with ba PWV, systolic BP and MAP. After adjustment for covariates, one standard deviation increase in ba PWV resulted in a 2-fold increase in the odds of being PiB+. ApoE-4 status was not associated with PWV. Additionally, high white matter disease burden, but not total gray matter volume, was associated with increased cf PWV (p<0.01), hf PWV (p=0.03), SBP (p=0.05) and MAP (p=0.06). Conclusions: The adverse effects of hypertension and vascular stiffness on cerebral small vessel disease is one of the most important hypotheses as to the determinants of amyloid deposition and AD. This is the first report of a possible association between vascular stiffness, BP and in vivo amyloid deposition in non-demented individuals.

Download Full-text

Physiology and Clinical Relevance of Enlarged Perivascular Spaces in the Aging Brain

Neurology ◽

10.1212/wnl.0000000000013077 ◽

2021 ◽

pp. 10.1212/WNL.0000000000013077

Author(s):

Corey W Bown ◽

Roxana O Carare ◽

Matthew S Schrag ◽

Angela L Jefferson

Keyword(s):

Fluid Transport ◽

Small Vessel Disease ◽

Treatment Strategies ◽

Small Vessel ◽

Aging Brain ◽

Perivascular Spaces ◽

Vessel Disease ◽

Clinical Consequences ◽

The Brain

Perivascular spaces (PVS) are fluid filled compartments that are part of the cerebral blood vessel wall and represent the conduit for fluid transport in and out of the brain. PVS are considered pathologic when sufficiently enlarged to be visible on magnetic resonance imaging. Recent studies have demonstrated that enlarged PVS (ePVS) may have clinical consequences related to cognition. Emerging literature points to arterial stiffening and abnormal protein aggregation in vessel walls as two possible mechanisms that drive ePVS formation. In this review, we describe the clinical consequences, anatomy, fluid dynamics, physiology, risk factors, and in vivo quantification methods of ePVS. Given competing views of PVS physiology, we detail the two most prominent theoretical views and review ePVS associations with other common small vessel disease markers. As ePVS are a marker of small vessel disease and ePVS burden is higher in Alzheimer’s disease, a comprehensive understanding about ePVS is essential in developing prevention and treatment strategies.

Download Full-text

IC-P-018: Arterial stiffness is associated with amyloid deposition in the brain independent of blood pressure

Alzheimer s & Dementia ◽

10.1016/j.jalz.2013.05.019 ◽

2013 ◽

Vol 9 ◽

pp. P19-P20 ◽

Cited By ~ 1

Author(s):

Timothy Hughes ◽

Lewis Kuller ◽

Emma Barinas-Mitchell ◽

Eric McDade ◽

Rachel Mackey ◽

...

Keyword(s):

Blood Pressure ◽

Arterial Stiffness ◽

Amyloid Deposition ◽

The Brain

Download Full-text

Relationship of amyloid-β1–42 in blood and brain amyloid: Ginkgo Evaluation of Memory Study

Brain Communications ◽

10.1093/braincomms/fcz038 ◽

2019 ◽

Vol 2 (1) ◽

Cited By ~ 1

Author(s):

Oscar L Lopez ◽

William E Klunk ◽

Chester A Mathis ◽

Beth E Snitz ◽

Yuefang Chang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Pet Imaging ◽

Standardized Uptake Value ◽

Amyloid Plaques ◽

Amyloid Deposition ◽

Pittsburgh Compound B ◽

Blood Samples ◽

Apolipoprotein E4 ◽

The Brain ◽

Brain Amyloid Deposition

Abstract A blood test that predicts the extent of amyloid plaques in the brain and risk of Alzheimer’s disease would have important benefits for the early identification of higher risk of dementia and Alzheimer’s disease and the evaluation of new preventative therapies. The goal of this study was to determine whether plasma levels of amyloid-β1–42, 1–40 and the amyloid-β1–42/1–40 ratio among participants in the Pittsburgh centre of the Ginkgo Evaluation of Memory Study were related to the extent of brain fibrillar amyloid plaques measured in 2009 using Pittsburgh compound-B PET imaging, hippocampal volume, cortical thickness in the temporal lobe and white matter lesions. There were 194 participants who had Pittsburgh compound-B measurements in 2009 with the mean age of 85 years; 96% were white and 60% men. Pittsburgh compound-B positivity was defined as a standardized uptake value ratio of ≥1.57. Amyloid-β in blood was measured using a sandwich enzyme-linked immunosorbent assay developed by Eli Lilly and modified at the University of Vermont. All participants were nondemented as of 2008 at the time of study close out. The study sample included 160 with blood samples drawn in 2000–02 and 133 from 2009 and also had brain amyloid measured in 2009. All blood samples were analysed at the same time in 2009. Plasma amyloid-β1–42 was inversely related to the percent Pittsburgh compound-B positive (standardized uptake value ratio ≥1.57), β −0.04, P = 0.005. Practically all participants who were apolipoprotein-E4 positive at older ages were also Pittsburgh compound-B positive for fibrillar amyloid. Among apolipoprotein-E4-negative participants, quartiles of amyloid-β1–42 were inversely related to Pittsburgh compound-B positivity. In multiple regression models, plasma amyloid-β1–42 measured in 2000–02 or 2009 were significantly and inversely related to Pittsburgh compound-B positivity as was the amyloid-β1–42/1–40 ratio. There was a 4-fold increase in the odds ratio for the presence of Pittsburgh compound-B positivity in the brain in 2009 for the first quartile of amyloid-β1–42 as compared with the fourth quartile in the multiple logistic model. This is one of the first longitudinal studies to evaluate the relationship between amyloid-β1–42 in the blood and the extent of brain amyloid deposition measured by PET imaging using Pittsburgh compound-B. Our findings showed that remote and recent low plasma amyloid-β1–42 levels were inversely associated with brain amyloid deposition in cognitively normal individuals. However, changes in plasma amyloid-β1–42 over time (8 years) were small and not related to the amount of Pittsburgh compound-B.

Download Full-text

PACAP is expressed in sympathoexcitatory bulbospinal C1 neurons of the brain stem and increases sympathetic nerve activity in vivo

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00753.2007 ◽

2008 ◽

Vol 294 (4) ◽

pp. R1304-R1311 ◽

Cited By ~ 46

Author(s):

Melissa M. J. Farnham ◽

Qun Li ◽

Ann K. Goodchild ◽

Paul M. Pilowsky

Keyword(s):

Blood Pressure ◽

Brain Stem ◽

Sympathetic Nerve ◽

Sympathetic Nerve Activity ◽

Intrathecal Administration ◽

Ventrolateral Medulla ◽

Cell Group ◽

Nerve Activity ◽

The Brain

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neuropeptide present in the rat brain stem. The extent of its localization within catecholaminergic groups and bulbospinal sympathoexcitatory neurons is not established. Using immunohistochemistry and in situ hybridization, we determined the extent of any colocalization with catecholaminergic and/or bulbospinal projections from the brain stem was determined. PACAP mRNA was found in tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the C1-C3 cell groups. In the rostral ventrolateral medulla (RVLM), PACAP mRNA was found in 84% of the TH-ir neurons and 82% of bulbospinal TH-ir neurons. The functional significance of these PACAP mRNA positive bulbospinal neurons was tested by intrathecal administration of PACAP-38 in anaesthetized rats. Splanchnic sympathetic nerve activity doubled (110%) and heart rate rose significantly (19%), although blood pressure was unaffected. In addition, as previously reported, PACAP was found in the A1 cell group but not in the A5 cell group or in the locus coeruleus. The RVLM is the primary site responsible for the tonic and reflex control of blood pressure through the activity of bulbospinal presympathetic neurons, the majority of which contain TH. The results indicate 1) that pontomedullary neurons containing both TH and PACAP that project to the intermediolateral cell column originate from C1-C3 and not A5, and 2) intrathecal PACAP-38 causes a prolonged, sympathoexcitatory effect.

Download Full-text

Inhibition of NOX1 mitigates blood pressure increases in elastin insufficiency

Function ◽

10.1093/function/zqab015 ◽

2021 ◽

Author(s):

Angela Troia ◽

Russell H Knutsen ◽

Carmen M Halabi ◽

Daniela Malide ◽

Zu Xi Yu ◽

...

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Reactive Oxygen Species ◽

Systolic Blood Pressure ◽

Blood Pressure Response ◽

Reactive Oxygen ◽

Vascular Wall ◽

Vascular Stiffness ◽

Oxygen Species

Abstract Elastin insufficiency leads to the cardiovascular hallmarks of the contiguous gene deletion disorder, Williams-Beuren syndrome, including hypertension and vascular stiffness. Previous studies showed that Williams-Beuren syndrome deletions that extended to include the NCF1 gene were associated with lower blood pressure and reduced vascular stiffness. NCF1 encodes for p47phox, the regulatory component of the NOX1 NADPH oxidase complex, that generates reactive oxygen species in the vascular wall. Dihydroethidium and 8-hydroxyguanosine staining of mouse aortas confirmed that Eln heterozygotes (Eln+/-) had greater reactive oxygen species (ROS) levels than wild types (Eln+/+), a finding that was negated in vessels cultured without hemodynamic stressors. To analyze the Nox effect on elastin insufficiency, we utilized both genetic and chemical manipulations. Both Ncf1 haploinsufficiency (Ncf1+/-) and Nox1 insufficiency (Nox1-/y) decreased oxidative stress and systolic blood pressure in Eln+/- without modifying vascular structure. Chronic treatment with apocynin, a p47phox inhibitor, lowered systolic blood pressure in Eln+/-, but had no impact on Eln+/+ controls. In vivo dosing with phenylephrine produced an augmented blood pressure response in Eln+/- relative to Eln+/+, and genetic modifications or drug-based interventions that lower Nox1 expression reduce the hypercontractile response to phenylephrine in Eln+/- mice to Eln+/+ levels. These results indicate that the mechanical and structural differences caused by elastin insufficiency leading to oscillatory flow can perpetuate oxidative stress conditions which are linked to hypertension, and that by lowering the Nox1-mediated capacity for vascular ROS production, blood pressure differences can be normalized.

Download Full-text

Abstract 13: Relations of Midlife Exercise Blood Pressure, Heart Rate and Fitness to Late Life Brain Structure and Function

Circulation ◽

10.1161/circ.131.suppl_1.13 ◽

2015 ◽

Vol 131 (suppl_1) ◽

Author(s):

Nicole L Spartano ◽

Jayandra J Himali ◽

Alexa S Beiser ◽

Charles DeCarli ◽

Ramachandran S Vasan ◽

...

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Frontal Lobe ◽

Cognitive Performance ◽

Brain Aging ◽

Later Life ◽

Older Age ◽

Vascular Stiffness ◽

Response To Exercise ◽

The Brain

Background: Exaggerated blood pressure (BP) and vascular stiffness have been associated with lower cognitive performance and brain atrophy in older age. The brain is a high-flow, low impedance organ that is susceptible to fluctuation in BP. Poor cardiovascular (CV) fitness is also emerging as a factor associated with cognitive decline in older age. The BP and heart rate (HR) response to exercise are impacted by CV fitness; and exercise BP is also highly determined by vascular stiffness. The objective of this investigation was to examine whether poor fitness and exaggerated BP and HR response to exercise in midlife are associated with worse brain morphology in later life. Methods: A subset of Framingham Offspring Study participants (n=1340, 54.5% F) free from dementia and CV disease underwent an exercise treadmill test (the modified Bruce protocol) in midlife [mean age of 41±9 y] and continued until exhaustion or until 85% HR maximum (age- and sex- predicted) was reached. Exercise test duration was used to estimate VO2max. BP and HR were measured during stage 2. MRI scans of the brain and neurocognitive tests (Trail Making Tests [Trails] B-A) were administered in later life [mean age of 59±9 y]. Results: A greater exercise systolic (S)BP and HR response at midlife was associated with smaller total cerebral brain volume (TCBV) in later life (β=-0.09 ±0.04, p=0.042; β=-0.10 ±0.05, p=0.033) after adjustment models including resting SBP and HR; an effect equal to approximately 0.5 y brain aging for every 11.1 mm Hg increase in SBP or 10 beats per min increase in HR. Higher estimated VO2max at midlife was associated with larger TCBV in later life (β=0.03 ±0.01, p=0.014). Additionally, greater exercise HR response at midlife was associated with smaller frontal lobe volume in later life (β=-0.012 ±0.05, p=0.002). Exercise diastolic (D)BP at midlife was associated with poorer performance on Trails B-A in later life (β=-0.009 ±0.004, p=0.017) and the achievement of target HR during exercise was associated with better performance on Trails B-A in later life (β=0.03 ±0.01, p=0.044). Resting SBP at midlife was associated with greater white matter hyperintensity volume in later life (β=0.05 ±0.02, p=0.031); and resting SBP and DBP at midlife were also associated with smaller frontal lobe volume in later life (β=-0.17 ±0.07, p=0.011; β=-0.21 ±0.10, p=0.030). Conclusion: Our investigation provides new evidence that lower midlife fitness and worse exercise BP and HR responses are associated with smaller brain volumes and poorer cognitive performance nearly two decades later. Promotion of midlife physical fitness may be an important step towards ensuring healthy brain aging in the population.

Download Full-text

P2-021: SELF-REPORTED OMEGA-3 SUPPLEMENT USE IS ASSOCIATED WITH LOWER BRAIN AMYLOID DEPOSITION AND HIGHER CEREBROVASCULAR CONDUCTANCE IN NON-DEMENTED OLDER ADULTS

Alzheimer s & Dementia ◽

10.1016/j.jalz.2019.06.1243 ◽

2019 ◽

Vol 15 ◽

pp. P578-P578

Author(s):

Carolyn Kaufman ◽

McKyla Chavez ◽

Eric D. Vidoni ◽

Sandra A. Billinger ◽

Jeffrey M. Burns

Keyword(s):

Older Adults ◽

Amyloid Deposition ◽

Omega 3 ◽

Supplement Use ◽

Brain Amyloid Deposition

Download Full-text

Pure tone audiometry and cerebral pathology in healthy older adults

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2019-321897 ◽

2019 ◽

Vol 91 (2) ◽

pp. 172-176 ◽

Cited By ~ 4

Author(s):

Thomas Parker ◽

David M Cash ◽

Chris Lane ◽

Kirsty Lu ◽

Ian B Malone ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Pure Tone ◽

Small Vessel Disease ◽

Pure Tone Audiometry ◽

Amyloid Deposition ◽

White Matter Hyperintensity ◽

Disease Pattern ◽

Β Amyloid

BackgroundHearing impairment may be a modifiable risk factor for dementia. However, it is unclear how hearing associates with pathologies relevant to dementia in preclinical populations.MethodsData from 368 cognitively healthy individuals born during 1 week in 1946 (age range 69.2–71.9 years), who underwent structural MRI, 18F-florbetapir positron emission tomography, pure tone audiometry and cognitive testing as part of a neuroscience substudy the MRC National Survey of Health and Development were analysed. The aim of the analysis was to investigate whether pure tone audiometry performance predicted a range of cognitive and imaging outcomes relevant to dementia in older adults.ResultsThere was some evidence that poorer pure tone audiometry performance was associated with lower primary auditory cortex thickness, but no evidence that it predicted in vivo β-amyloid deposition, white matter hyperintensity volume, hippocampal volume or Alzheimer’s disease-pattern cortical thickness. A negative association between pure tone audiometry and mini-mental state examination score was observed, but this was no longer evident after excluding a test item assessing repetition of a single phrase.ConclusionPure tone audiometry performance did not predict concurrent β-amyloid deposition, small vessel disease or Alzheimer’s disease-pattern neurodegeneration, and had limited impact on cognitive function, in healthy adults aged approximately 70 years.

Download Full-text