Cardiovascular and cerebrovascular diseases are the most common cause of death among
older people in the United States, accounting for ~1/3 of all deaths in the US at
the age of 65, and nearly 2/3 at the age of 85. With a projected increase in the number
of adults over 65 years old from 12 to 22% in the next 30 years, addressing age-related
vascular diseases is of critical importance, as the annual cost to care for the older
population is expected to more than double in that same time frame. Aging in the brain
is characterized by a vast array of functional and structural alterations of the microcirculation,
contributing to the pathogenesis of a range of age-related diseases including vascular
cognitive impairment (VCI), Alzheimer's disease (AD), and mild cognitive impairment
(MCI). The collection of articles published in the Research Topic titled: “New Developments
in Understanding Brain and Cerebromicrovascular Aging: Toward Prevention of Vascular
Cognitive Impairment and Alzheimer's Disease” highlights the recent growing interest
and understanding of the role of the aging vasculature in the context of the age-related
loss of cognitive function. The goal of this collection is to stimulate interest and
gather evidence that relates to the mechanisms underlying the neurodegenerative diseases
that associate with aging, with particular emphasis on treatment and interventions
that aim to prevent or delay the onset of vascular cognitive impairment and Alzheimer's
disease.
VCI and AD are the most common forms of cognitive disorder associated with cerebrovascular
diseases and are related to increased morbidity and mortality among the older population
(Wiesmann et al., 2013). Growing evidence highlighted in this Research Topic emphasizes
the multifactorial nature of age-related cerebrovascular disease. Despite the evidence
that reversal of vascular dementias has shown mixed results, we now understand that
many of the risk factors are largely preventable. Such risk factors examined in this
special issue include the effects of obesity, sedentary lifestyle, eating behaviors,
hypertension, diabetes, circulating endocrine factors, and others. The current challenges
and efforts in the field will also be briefly explored, while novel biomarkers of
cerebrovascular disease and AD will be discussed.
Bliss et al. investigate the effects of aerobic exercise training on cerebrovascular
and cognitive function in sedentary, obese, older adults. In their study, the authors
showed that cerebrovascular function and cognition improved following 16 weeks of
exercise and determined the presence of a dose-response relationship between the amount
of exercise sessions performed and cerebrovascular reactivity to cognitive stimuli.
Lifestyle interventions aimed at delaying or preventing age-related pathophysiology
include exercise (Lucas et al., 2015; Bliss et al., 2021) and alterations in diet
(Dobreva et al., 2022; Maroto-Rodriguez et al., 2022) [i.e. caloric restriction, intermittent
fasting (Balasubramanian et al., 2020; Bray et al., 2022), or methionine restriction].
These highly translatable interventions have been shown to be effective in mediating
increased health and lifespan in mice and other model organisms. Thelen and Brown-Borg
reviewed the existing evidence to better understand the therapeutic potential of diets
to act as a future treatment option for AD patients.
Circulating insulin-like growth factor-1 (IGF-1) deficiency is a well-known predictor
of cognitive decline. For instance, previous studies established a causal link among
age-related decline in circulating levels of IGF-1, neurovascular dysfunction, and
cognitive impairment (Tarantini et al., 2021). Miller et al. further describe how
IGF-1 deficiency is associated with increased susceptibility to cerebral microhemorrhages
and signs of microvascular degeneration in the retina in response to hypertension.
The formation of microhemorrhages, which associate with cognitive impairments, psychiatric
disorders, and gait dysfunctions in patients is also caused by mild traumatic brain
injury (mTBI). In this context, Toth et al. have investigated the effect of mTBI on
cerebral microhemorrhages in aging and have reported that aging enhances the formation
of parietal and occipital microhemorrhages after mTBIs.
The properties of the brain cerebral microvasculature can be also studied in the retina
(Newman, 2013), as those micro vessels are closely related to those in the brain (Ptito
et al., 2021). In addition to the work from Miller et al., illustrated above, Cheng
et al. utilized the retina as model to study the association between diabetic retinopathy
and cognitive impairment in this extensive systematic review. This timely work better
examines the correlation of diabetic retinopathy with cognitive impairment, which
has not been well-studied yet.
Normal brain function is dependent on moment-to-moment adjustment of cerebral blood
flow to match the increased demands of active brain regions (Masamoto and Vazquez,
2018; Yabluchanskiy et al., 2021). The underlying biological mechanism termed neurovascular
coupling (NVC) is dependent on the production of the endothelium-derived vasodilator
molecule nitric oxide in response to multiple mediators released from activated astrocytes.
Csipo et al. studied how geriatric sepsis affects endothelial dysfunction and impaired
NVC responses precede cognitive impairment in a mouse model of geriatric sepsis, suggesting
that sepsis-associated endothelial dysfunction and impairment of NVC responses may
contribute to long-term cognitive deficits in older sepsis survivors. In addition,
Liu et al. aimed to explore the characteristics and contributions of cerebral hemodynamics
and carotid atherosclerosis to cognitive dysfunction. The authors discovered that
pathological changes in macrovascular structure and function are correlated with cognitive
impairment in dementia. This is intriguing as recent studies have shown that macrovascular
aberrations closely associated with decreased microvascular health in aging (Xu et
al., 2017). Shabaan et al. were also interested in examining the link between cognition
and cerebrovascular reactivity in midlife women with both preeclampsia and maternal
vascular malperfusion (MVM). Their data suggested that MVM in women with preeclampsia
is a promising sex-specific indicator of cerebrovascular integrity in midlife (Shabaan
et al.).
Another challenge in the field of cerebromicrovascular aging has been identifying
a reliable indicator or biomarker to detect patients with different forms of dementia
at an early stage (Zampino et al., 2022). Liu et al. showed that basal ganglia perivascular
spaces were associated with increased cardiovascular risk burden and regional differences
in cerebral blood flow and gray matter volume, thereby advancing the idea that perivascular
spaces are an important associated phenotypic indicator of VCI with a larger population
of cognitively intact individuals. Similarly, Yao et al. suggested that in a population
of frail patients with cardiovascular disease the urinary 8-oxoGsn (a typical marker
of oxidative modification of RNA) adjusted by urinary creatine levels, may be a useful
indicator for the early screening of MCI. In their study, Sun et al. searched for
an endothelial-specific biological marker to better understand the pathogenesis of
cerebral small vessel disease (CSVD). Intriguingly, they found a relationship between
ADAMTS13 activity and white matter hyperintensity (WMH), subcortical infarction, but
not with cerebral microhemorrhage. In addition, ADAMTS13 (which regulates the activity
of endothelium-derived von Willebrand factor by cutting it into smaller, less active
molecules) may play an essential role in the progression of CSVD. Another typical
marker that associates with CSVD are WMHs. In their study Bauer et al. perform an
extensive assessment of WMH volume and location. Notably, their results suggest that
white matter microstructure may be a better predictor of WMHs volume than either brain
iron levels or cerebral blood flow (CBF) but also draws attention to the possibility
that some early WMH markers may be location specific. Furthermore, Vettore et al.
add that the association between WMH burden and connectivity strength, during resting-state
functional networks, is different between amnestic and non-amnestic MCI patients.
Despite the exploratory nature of this study, these results suggest that clinical
profiles reveal mechanistic interactions that may play a critical role in the classification
of diagnostic vs. prognostic conditions. In another study, Liu et al. developed an
innovative transfer learning model based on speech and natural language processing
(NLP) technology to effectively improve the early diagnosis of AD.
Genetic variability is another interesting factor that can play a major effect in
the development of cerebral vasculature (Bogorad et al., 2019), and as a determinant
for age-related cerebrovascular disease and AD, as demonstrated in both clinical and
experimental studies (Korstanje et al., 2021; Kulminski et al., 2022). Recent genetic
mutation studies done in rodents have elucidated how different genetic backgrounds
can significantly affect flow-mediated outward remodeling in the bilateral posterior
communicating arteries after unilateral occlusion of a middle cerebral artery. Therefore,
Eto et al. aimed to investigate the relationship between anatomical variations in
the circle of Willis in cerebrovascular disease. This study sets up an important framework
in which future investigations can further expand to understand what genetic variants
are critical in determining anatomical variations in the circle of Willis, thus increasing
vulnerability to age-related vascular disease. Additionally, Ehret et al. draw attention
to an important point mutation in Notch3 (N3), which is known to cause Cerebral Autosomal
Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL).
N3 is expressed in neural stem and progenitor cells in the hippocampus, where the
authors previously demonstrated that it is a critical regulator of precursor cell
proliferation and differentiation in the neurogenic niche of the murine hippocampus.
Based on the previous results, they now suggest that N3 might exert regulatory influences
on neuronal plasticity that could impact hippocampus-dependent learning and memory.
The hippocampus together with the pre-frontal cortex constitute a very important brain
area involved in the regulation of emotion and cognition. Qi et al. described how
a bilateral hippocampal microinjection of streptozotocin can induce AD-like behavioral
performance in mice, and adaptive changes in synaptic plasticity against neuroinflammatory
and endocrinal injuries. The authors interpret these findings and hypothesize the
underlying mechanisms to be associated with the inadequate balance in the hippocampal
expression of the key proteins involved in Wnt signaling pathway.
Lastly, Takeuchi et al. discovered that the RNA transcription analysis of metabolism
related genes in circulating white blood cells (WBCs) has the potential to provide
significant information relating to impaired cell-cell interaction between WBCs and
endothelial cells of aged mice. Additionally, this can serve as a tool to evaluate
the change of the cell-cell interaction caused by various treatments or diseases.
Author contributions
ST: Conceptualization, funding acquisition, writing-original draft, and writing-review
and editing. MS and SN: Writing-review and editing. All authors contributed to the
article and approved the submitted version.
Funding
This work was supported by grants from the National Institute on Aging (NIA R03AG070479
and NIA K01AG073614), the American Heart Association AHA CDA941290, the NIA-supported
Geroscience Training Program in Oklahoma (T32AG052363), the NIA-supported Oklahoma
Nathan Shock Center, and the NIGMS supported Center of Biomedical Research Excellence
(CoBRE) (1P20GM125528-01A1).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.
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