Aims

To determine the physiological functions of human high-density lipoprotein (HDL) particles on human endothelial cells cultured alone or in context with other cells of the neurovascular unit.

Abstract Body

Aims: To determine the physiological functions of human high-density lipoprotein (HDL) particles on human endothelial cells cultured alone or in context with other cells of the neurovascular unit.

Methods: We used primary and human iPSC cells in standard monoculture and in a 3-dimensional bioengineered arterial model of the perfused human cerebrovasculature to study cerebral amyloid angiopathy (CAA) as measured by Aβ deposition and transport, and Aβ-induced endothelial inflammation measured by monocyte binding.

Results: HDL vascular Aβ accumulation independently of its principal binding protein, scavenger receptor (SR)-BI, in contrast to the SR-BI-dependent mechanism by which HDL prevents Aβ-induced vascular inflammation. HDL also reduces CAA through four mechanisms: i) altering Aβ binding to collagen-I, ii) forming a complex with Aβ that maintains its solubility, iii) diminishing collagen-I expression by smooth-muscle cells (SMC), and iv) attenuating Aβ uptake in SMC perhaps by reducing LRP1 expression. Finally, HDL particles enriched in apolipoprotein (apo)E appear to be the major drivers of these effects.

Conclusions: Circulating HDL, particularly HDL particles with apoE, may have beneficial effects on the cerebrovasculature, acting from the lumen to facilitate Ab egress from the brain and reduce cerebrovascular inflammation.

Methods

We used primary and human iPSC cells in standard monoculture and in a 3-dimensional bioengineered arterial model of the perfused human cerebrovasculature to study cerebral amyloid angiopathy (CAA) as measured by Aβ deposition and transport, and Aβ-induced endothelial inflammation measured by monocyte binding.

Results

HDL vascular Aβ accumulation independently of its principal binding protein, scavenger receptor (SR)-BI, in contrast to the SR-BI-dependent mechanism by which HDL prevents Aβ-induced vascular inflammation. HDL also reduces CAA through four mechanisms: i) altering Aβ binding to collagen-I, ii) forming a complex with Aβ that maintains its solubility, iii) diminishing collagen-I expression by smooth-muscle cells (SMC), and iv) attenuating Aβ uptake in SMC perhaps by reducing LRP1 expression. Finally, HDL particles enriched in apolipoprotein (apo)E appear to be the major drivers of these effects.

Conclusions

Circulating HDL, particularly HDL particles with apoE, may have beneficial effects on the cerebrovasculature, acting from the lumen to facilitate Aβ egress from the brain and reduce cerebrovascular inflammation.

Abstract Body

Vascular contributions to cognitive impairment and dementia (VCID) is an important and understudied cause of cognitive impairment, often co-morbid with Alzheimer's disease and other neurodegenerative conditions. Diffuse white matter disease (DWD) is apparent on magnetic resonance imaging (MRI), appearing as white matter hyperintensities (WMH). It has long been considered to be a consequence of cerebrovascular pathology; more specifically small vessel disease resulting from hypertension and microinfarcts.

Much like the pathologic angiogenesis that occurs in retinopathies, pathologic angiogenesis in the brain results in blood-brain barrier leakage and, counterintuitively, tissue ischemia. We have examined plasma and CSF angiogenic mediators in a cohort of 120 research participants who also have a range of cognitive impairments and severity of WMH changes on MRI. We found that several members of the vascular endothelial growth factor (VEGF) family, in particular placental growth factor (PlGF), which is significantly associated with WMH growth and cognitive measures, especially executive function measures. We haev examined post-mortem autopsy tissue to determine PlGF expression in the human bran and we foudn strong immunostaining in the white matter of individuals with small vessel disease, primarilary perivascular labeling. Such staining was significantly less in the brains of age-matched, pathology-free individuals. We also performed exosome studies in plasma and found that the primary source of PlGF in the plasma is astrocytic, and also there is some PlGF in endothliel exosomes.

We hypothesize that PlGF, and related angiogenic mediators, result in pathologic angiogenesis, with leaky, tortuous vessels and surrounding inflammation, leading to WMH and cognitive impairment.

Abstract Body

Abstract Body

“Neurovascular bases of neurodegeneration”

Costantino Iadecola, MD

The brain lacks energy reserves and is vitally dependent on a continuous and well-regulated delivery oxygen and glucose through the cerebral blood supply. Structural and functional alterations of cerebral blood vessels have emerged as key correlates of cognitive impairment. The concept of “neurovascular unit” (NVU) highlights the close developmental, structural, and functional interactions between brain cells and cerebral blood vessels, and their coordinated reaction to injury. Comprised of neurons, glia, perivascular cells, e.g., perivascular macrophages, and vascular cells, the NVU is responsible for matching the delivery of blood to the brain with local energy needs dictated by brain activity. The NVU is also involved in regulating the blood-brain barrier, the clearance of metabolic byproducts, the trafficking of immune cells, and in providing trophic support to brain cells. NVU dysfunction alters the homeostasis of the brain microenvironment in regions involved in cognition leading to cognitive impairment. Thus, neurovascular dysfunction is observed not only in vascular cognitive impairment, but also in Alzheimer’s disease, attesting to the significant overlap between these conditions. In addition, major risk factors for cognitive impairment, such as hypertension, ApoE4 genotype, and high salt intake, are also associated with neurovascular dysfunction. Activation of innate immunity, vascular oxidative stress, and inflammation are major pathogenic factors. These data reveal a previously appreciated link between vascular risk factors and neurodegenerative mediators, which may have major diagnostic and therapeutic implications for both vascular and neurodegenerative dementias.

Abstract Body

Background:

Benefits of blood pressure (BP) lowering for the prevention of dementia or cognitive impairment (CI) are unclear. This review aimed to determine the association of BP lowering with dementia or CI.

Methods:

Randomized clinical trials (RCTs) that evaluated the association of BP lowering on cognitive outcomes were included. Random-effects meta-analysis models were used to report pooled treatment effects and Confidence Intervals. The primary outcome was dementia or CI. Secondary outcomes were cognitive decline and changes in cognitive test scores.

Results:

Fourteen RCTs were eligible for inclusion (96,158 participants).12 reported the incidence of dementia (or composite of dementia and CI [3 trials]) on follow-up and were included in the primary meta-analysis. 8 reported cognitive decline, and 8 reported changes in cognitive test scores. Mean (SD) age was 69 (5.4) years and 40,617 (42.2%) were women. Mean systolic baseline BP was 154(14.9)mmHg and mean diastolic BP was 83.3(9.9)mmHg. Mean duration of follow-up was 49.2 months.

BP lowering with antihypertensive agents compared with control was significantly associated with a reduced risk of dementia or CI (12 trials; 92,135 participants) (7.0% vs 7.5% of particpants; odds ratio[OR], 0.93 [95%CI, 0.88-0.98]; absolute risk reduction, 0.39% [95%CI, 0.09%-0.68%];I2 = 0.0%) and cognitive decline (8 trials) (20.2% vs 21.1% of participants; OR, 0.93 [95%CI, 0.88-0.99]; absolute risk reduction, 0.71% [95%CI, 0.19%-1.2%];I2 = 36.1%). BP lowering was not significantly associated with change in cognitive test scores.

Conclusions:

BP lowering with antihypertensive agents compared with control was significantly associated with a lower risk of incident dementia or CI

Aims

Different biomarkers of neuroinflammation and cerebrovascular dysfunction are thought to be associated with neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), even during their preclinical and prodromal stages. However, little is known so far about associations between inflammatory markers and white matter lesions (WML) detected with magnetic resonance imaging (MRI).

Methods

We included 582 cognitively unimpaired (CU) elderly, 279 patients with mild cognitive impairment (MCI), and 175 PD patients. CSF samples were analyzed for interleukin (IL)–6, IL-7, IL-8, IL-15, IL-16, interferon-gamma induced protein-10 (IP-10), monocyte chemoattractant protein 1 (MCP1), intercellular adhesion molecule 1(ICAM-1), vascular adhesion molecule 1 (VCAM-1), placental growth factor (PIGF), and fms-related tyrosine kinase 1 (Flt-1) as well as vascular endothelial growth factor (VEGF). WML volumes were determined from MRI for all subjects.

Results

In CU, more WML was associated with higher levels of PIGF (β=0.007, p<0.001) and lower levels of sFLT1 (β=-0.018, p<0.001), whereas in MCI more WML volume was associated with higher levels of IL-16 (β=0.118, p<0.001), higher levels of PIGF (β=0.007, p<0.001), and higher levels of VEGF (β=0.105, p=0.003). Associations were still significant after corrections for multiple comparisons. In PD higher levels of WML were associated with VEGF (β=0.374, p=0.007) and PLGF (β=0.321, p=0.019), however those associations were not significant after correction for multiple comparison.

Conclusions

CSF markers of vascular system, such as VEGF and PLGF, are associated with cerebrovascular injury in prodromal AD and PD.

Aims

Increasing evidences suggest that endothelial dysfunction is involved in the AD pathophysiological processes. Upregulation of cell adhesion molecules (CAMs) reflects endothelial dysfunction. Inflammatory and microbiota mediators (short chain fatty acids, SCFAs) affect CAMs expression. This study aimed at evaluating CAMs levels and their association with SCFAs and inflammatory mediators along the AD continuum.

Methods

Participants were 44 cognitively intact (CI) older adults with known APOE genotype (cohort 1) and, 10 CI, 33 amyloid-negative (Amy-) and 29 amyloid-positive (Amy+) cognitively impaired patients (cohort 2). CAMs (ICAM-1, 2, 3, PECAM-1, NCAM, PSGL-1, E- and P-selectin) were measured by flow cytometry, SCFAs (acetate, valerate, butyrate) with mass spectrometry, inflammatory mediators (pro- anti-inflammatory cytokines) by RT-PCR. CAMs levels was compared between APOEe4-carriers (possibly at the beginning of the AD continuum) and non-carriers (cohort 1) and, among CI, Amy+ (at a later stage of the AD continuum) and Amy- (cohort 2). In cohort 2, we also evaluated the association of CAMs with SCFAs and inflammatory mediators.

Results

Higher expression of P-Selectin and PSGL-1 was reported in APOEe4-carriers (p<.046 vs non-carriers) and in Amy+ patients (p<.011 vs Amy-, IC). Amy+ also showed higher NCAM, PECAM-1 and ICAM-2 levels (p<.023, vs Amy-, IC). High CAMs levels were associated with elevated levels of acetate, valerate and pro-inflammatory cytokines and with low levels of butyrate and anti-inflammatory cytokines (|rho|<0.51, p<.024).

Conclusions

These results suggest that endothelial dysfunction is already present at the beginning of the AD continuum, it is associated with microbial and inflammatory mediators and might contribute to AD processes.

Abstract Body

Brain aging leads to cognitive decline and is the main risk factor for sporadic forms of neurodegenerative diseases including Alzheimer’s disease. While brain cell- and tissue-intrinsic factors are likely key determinants of the aging process recent studies document a remarkable susceptibility of the brain to circulatory factors. Thus, blood borne factors from young mice or humans are sufficient to slow aspects of brain aging and improve cognitive function in old mice and, vice versa, factors from old mice are detrimental for young mice and impair cognition. In trying to understand the molecular basis of these observations we found evidence that the cerebrovasculature is an important target and that brain endothelial cells show prominent age-related transcriptional changes in response to plasma. We discovered that plasma proteins are taken up broadly into brain endothelial cells and that this process various greatly between individual cells and with aging. We are exploring the relevance of these findings for neurodegeneration and potential application towards therapies.