Fight Aging! Newsletter, July 25th 2022

Parkinson's disease (PD) is an age-related brain disease that is associated with motivation and cognitive disorders and the assembly of alpha-synuclein (α-syn); there is no effective therapeutic treatment for this condition. Along with tissue dysfunction, the typical senescence-associated secretory phenotype is significantly characterized by the generation of interleukin-6 (IL-6) and interleukin-1β (IL-1β). Indeed, the accumulation of senescent cells is associated with a range of age-related diseases as well as neurodegenerative diseases. However, it is still unclear how senescence in the brain contributes to PD and what role it might play in therapeutic strategies of PD.

It had been reported that senescent cells could give rise to local and systemic inflammation and contribute to neurodegeneration in neurodegeneration diseases like PD. In addition, direct exposure to amyloid-β (Aβ) was shown to cause senescence in oligodendrocyte precursor cells (OPCs), and the clearance of OPCs by senolytic therapy alleviated Aβ-associated inflammation and restored cognitive deficits in Alzheimer's disease mice, thus illustrating the potential for senescence clearance to be used in clinical practice. Moreover, senescent cells play a role in the initiation and progression of tau-mediated disease, and targeting of senescent cells may provide a therapeutic avenue for the treatment of such pathologies. Therefore, eliminating senescent cells may hold therapeutic promise for alleviating the symptoms of PD.

In this study, chiral gold nanoparticles (NPs) with different helical directions were synthesized to selectively induce the apoptosis of senescent cells under light illumination. By modifying anti-B2MG and anti-DCR2 antibodies, senescent microglia cells could be cleared by chiral NPs without damaging the activities of normal cells under illumination. Mechanistic studies revealed that the clearance of senescent cells was mediated by the activation of the Fas signaling pathway. The in vivo injection of chiral NPs successfully confirmed that the elimination of senescent microglia cells in the brain could further alleviate the symptoms of PD mice in which the alpha-synuclein (α-syn) in cerebrospinal fluid decreased from 83.83 ± 4.76 ng/mL to 8.66 ± 1.79 ng/mL and the pathological symptoms of the PD mice were greatly improved after two months of treatment.

Changes in arterial structure and function accompanying aging lead to an increased risk of cardiovascular diseases (CVD). Thus, understanding the mechanisms by which age affects the vascular system can help to avoid altogether or to reduce the high risk of developing cardiovascular diseases in elderly people. Several new (preliminary) clinical studies have found that the most important vascular changes occur with aging and described 2 key traits: (1) generalized endothelial dysfunction and (2) stiffness of the central artery. As for generalized endothelial dysfunction, vascular aging alters the endothelium function and the cells that cover the lumen of blood vessels. Endothelial dysfunction includes a decrease in vasodilatory and antithrombotic properties, with an elevation in oxidative stress and inflammatory cytokines, which favor atherogenesis and thrombosis and predispose to cardiovascular diseases. Both human and experimental studies have proven a reduction in the bioavailability of nitric oxide (NO), a major mediator of vasorelaxation and antiatherogenic processes that are the foundation of age-related endothelial dysfunction.

With aging, the elasticity of arteries, especially the aorta, decreases. This leads to arterial stiffness, which is, at least in part, the result of gradual fragmentation and loss of elastin fibers and accumulation of stiffer collagen fibers. The risk of hypertension and the range of various disorders are tightly linked to increased arterial stiffness. Vascular calcification is specific for aging and vascular stiffness. The development of calcification is accelerated in patients with hypertension, diabetes mellitus, and other disorders. However, an exact mechanism linking calcification with aging is still unclear.

During the process of aging, a shift towards the pro-inflammatory phenotype with elevated expression of inflammatory cytokines, adhesion molecules, and chemokines from endothelial cells (ECs) has been observed. These pro-inflammatory cytokines include interleukin (IL)-6, IL-1β, cellular adhesion molecules, tumor necrosis factor-alpha (TNF-α), and monocyte chemoattractant protein-1. Prolonged exposure to TNF-α leads to early aging of the endothelium, which can be avoided by suppressing the activation of NF-KB. This fact gives rise to the hypothesis that inflammation leads to premature aging of the endothelium. Thus, human aging is a chronic, systemic and low-grade pro-inflammatory condition, and this phenomenon has been defined as "inflammaging".

All body systems age, lose their performance, and structural disorders accumulate. The cardiovascular system is no exception. And it is cardiovascular diseases that occupy a leading position as a cause of death, especially among the elderly. The aging of the cardiovascular system is well described from a mechanical point of view. Moreover, it is known that at the cellular level, a huge number of mechanisms are involved in this process, from mitochondrial dysfunction to inflammation. It is on these mechanisms, as well as the potential for taking control of the aging of the cardiovascular system, that we focused on in this review.

Age-related hearing loss (ARHL), or presbyacusis, is a type of sensorineural hearing loss that primarily affects the elderly. However, the age of onset, rate of decline, and severity of hearing loss vary widely. ARHL is the most common sensory disorder, with a high economic impact. The World Health Organization (WHO) estimates that by 2050, 2.5 billion people, predominantly over 60, will be living with some degree of hearing loss . Despite the high prevalence of this sensory disorder, there is a paucity of both preventative and treatment strategies other than prosthetic devices (hearing aids and cochlear implants).

Presbyacusis typically presents as bilateral, progressive, and irreversible. The increasing prevalence of presbyacusis may be attributable to environmental factors, notably noise exposure and the rise in metabolic diseases. This sensory disorder can be characterised by reduced hearing sensitivity and speech understanding in background noise, slowed central processing of acoustic information, and impaired localisation of sound sources. Hearing loss affects high frequencies initially and eventually spreads to lower frequencies involved in speech understanding. Untreated hearing impairment contributes to social isolation, loss of self-esteem, depression, and cognitive decline. Even mild levels of hearing loss increase the long-term risk of cognitive decline and dementia.

ARHL has a complex pathophysiology linked to genetic risk factors that determine the rate and extent of cochlear degeneration. However, the severity of the hearing loss is also influenced by previous otological diseases, chronic illnesses, cumulative noise exposure, use of ototoxic drugs, and lifestyle. Moreover, this condition has been associated with numerous comorbidities, including dementia, frailty, Alzheimer's disease, and type II diabetes. A common trait of these disorders is chronic inflammation in target organs.

Various stimuli can sustain inflammaging, including pathogens, cell debris, nutrients, and gut microbiota. As a result of ageing, the immune system can become defective, leading to the accumulation of unresolved inflammatory processes in the body. Gut microbiota plays a central role in inflammaging because it can release inflammatory mediators and crosstalk with other organ systems. A proinflammatory gut environment associated with ageing could result in a leaky gut and the translocation of bacterial metabolites and inflammatory mediators to distant organs via the systemic circulation. Here, we postulate that inflammaging, as a result of immunosenescence and gut dysbiosis, accelerates age-related cochlear degeneration, contributing to the development of ARHL. Age-dependent gut dysbiosis was included as a hypothetical link that should receive more attention in future studies.

DNA damage is now widely implicated in aging and the pathophysiology of age-related neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD). However, emerging evidence suggests that DNA damage and DNA repair are not only induced by pathological conditions. The same processes involved in neurodegeneration as we age are also involved in fundamental physiological functions of neurons that are related to neural plasticity. Hence, DNA damage and repair are associated with neural plasticity, implying an important role for these processes in neuronal function. Furthermore, in neurodegenerative diseases the selective death of specific groups of neurons is present. This suggests that the unique properties of neurons may contribute to selective neurodegeneration in pathophysiology.

Several studies have shown that neuronal activity generates double strand breaks (DSBs) in cultured neurons. A recent study concluded that DSBs are generated physiologically to resolve topological limitations to gene expression in neurons. Topoisomerase enzymes participate in the overwinding or underwinding of DNA and thus they manage DNA topological constraints. Neuronal activity produces DSBs at specific loci in vitro by topoisomerase IIβ (TopIIβ), in the promoters of early response genes (ERGs, also called immediate early genes, IEGs) that are crucial for experience-driven changes to synapses, learning, and memory. Interestingly, the expression patterns of ERGs in response to neuronal stimulation correlated well with the formation and repair of activity-induced DSBs, implying that generation of DSBs and their subsequent repair are essential steps for proper gene function. Furthermore, DSBs produced during neuronal excitation were repaired within 2 hours of the initial stimulus, suggesting that this process employs rapid DNA repair mechanisms such as non-homologous end joining (NHEJ).

Dysfunction in these processes of DNA damage and repair is also related to a decline in cognitive function and neuronal death in neurodegenerative diseases. However, human post-mortem tissues represent the end-point stage of the disease. Hence studies examining these tissues cannot be used to determine whether DNA damage has a primary or secondary role in pathogenesis. Future studies on the relationship between plasticity and DNA damage may provide a better understanding of the cellular processes that contribute to higher order brain functions.

Distinct groups of neurons are affected in different neurodegenerative diseases, such as motor neurons in ALS or neurons of the entorhinal cortex in AD, and these cells are specialized to perform specific functions. Given that DNA damage and repair are important for the unique functions of neurons, which in turn depend on their activation, it is possible that the interplay between DNA damage and neural plasticity is unique for specific groups of neurons. This could operate through the activation of specific genes by DNA damage, which would differ depending on the type of neurons involved and their associated functions. Therefore, a better understanding of the interplay between DNA damage and neural plasticity is required, as well as dysfunction in these processes in disease. In particular, the inclusion of specific neuronal types may reveal the causes of selective neuronal death in distinct neurodegenerative diseases.

To date, no previous studies have examined therapeutic strategies directed at DNA damage and repair in relation to aberrant neural plasticity. However, this approach has the potential to identify novel treatments for impaired cognitive functions in neurodegenerative diseases associated with excessive DNA damage.

Researchers have shown that the misfolding, aggregation, and buildup of amyloid beta proteins in the brain plays a central role in Alzheimer's disease. Therefore, preventing and removing misfolded protein aggregates is considered a promising treatment for the disease. After multiple blood transfusions, the researchers found that the development of cerebral amyloid plaques in a transgenic mice model of Alzheimer's disease was reduced by 40% to 80%. This reduction also resulted in improved spatial memory performance in aged mice with the amyloid pathology, and lowered the rates of plaque growth over time.

While the exact mechanism by which this blood exchange reduces amyloid pathology and improves memory is currently unknown, there are multiple possibilities. One possible explanation is that lowering amyloid beta proteins in the bloodstream may help facilitate the redistribution of the peptide from the brain to the periphery. Another theory is that blood exchange somehow prevents amyloid beta influx, or inhibits the re-uptake of cleared amyloid beta, among other potential explanations.

Alzheimer's disease (AD) is the major form of dementia in the elderly population. The main neuropathological changes in AD patients are neuronal death, synaptic alterations, brain inflammation, and the presence of cerebral protein aggregates in the form of amyloid plaques and neurofibrillary tangles. Compelling evidence suggests that the misfolding, aggregation, and cerebral deposition of amyloid-beta (Aβ) plays a central role in the disease. Thus, prevention and removal of misfolded protein aggregates is considered a promising strategy to treat AD.

In the present study, we describe that the development of cerebral amyloid plaques in a transgenic mice model of AD (Tg2576) was significantly reduced by 40-80% through exchanging whole blood with normal blood from wild type mice having the same genetic background. Importantly, such reduction resulted in improvement in spatial memory performance in aged Tg2576 mice. The exact mechanism by which blood exchange reduces amyloid pathology and improves memory is presently unknown, but measurements of Aβ in plasma soon after blood exchange suggest that mobilization of Aβ from the brain to blood may be implicated. Our results suggest that a target for AD therapy may exist in the peripheral circulation, which could open a novel disease-modifying intervention for AD.

Alzheimer's disease (AD) is a common, progressive, and devastating neurodegenerative disorder that mainly affects the elderly. Microglial dysregulation, amyloid-beta (Aβ) plaques, and intracellular neurofibrillary tangles play crucial roles in the pathogenesis of AD. In the brain, microglia play roles as immune cells to provide protection against virus injuries and diseases. They have significant contributions in the development of the brain, cognition, homeostasis of the brain, and plasticity. Multiple studies have confirmed that uncontrolled microglial function can result in impaired microglial mitophagy, induced Aβ accumulation and tau pathology, and a chronic neuroinflammatory environment.

In the brain, most of the genes that are associated with AD risk are highly expressed by microglia. Although it was initially regarded that microglia reaction is incidental and induced by dystrophic neurites and Aβ plaques, nonetheless, it has been reported by genome-wide association studies that most of the risk loci for AD are located in genes that are occasionally uniquely and highly expressed in microglia. This finding further suggests that microglia play significant roles in early AD stages and they be targeted for the development of novel therapeutics.

In this review, we have summarized the molecular pathogenesis of AD, microglial activities in the adult brain, the role of microglia in the aging brain, and the role of microglia in AD. We have also particularly focused on the significance of targeting microglia for the treatment of AD.

Cerebral small vessel disease (CSVD) is one of the most important causes of vascular dementia. Immunosenescence and inflammatory response, with the involvement of the cerebrovascular system, constitute the basis of this disease. Immunosenescence identifies a condition of deterioration of the immune organs and consequent dysregulation of the immune response caused by cellular senescence, which exposes older adults to a greater vulnerability. A low-grade chronic inflammation status also accompanies it without overt infections, an "inflammaging" condition. The correlation between immunosenescence and inflammaging is fundamental in understanding the pathogenesis of age-related CSVD (ArCSVD).

The production of inflammatory mediators caused by inflammaging promotes cellular senescence and the decrease of the adaptive immune response. Vice versa, the depletion of the adaptive immune mechanisms favours the stimulation of the innate immune system and the production of inflammatory mediators leading to inflammaging. Furthermore, endothelial dysfunction, chronic inflammation promoted by senescent innate immune cells, oxidative stress and impairment of microglia functions constitute, therefore, the framework within which small vessel disease develops: it is a concatenation of molecular events that promotes the decline of the central nervous system and cognitive functions slowly and progressively.

Because the causative molecular mechanisms have not yet been fully elucidated, the road of scientific research is stretched in this direction, seeking to discover other aberrant processes and ensure therapeutic tools able to enhance the life expectancy of people affected by ArCSVD. Although the concept of CSVD is broader, this manuscript focuses on describing the neurobiological basis and immune system alterations behind cerebral aging. Furthermore, the purpose of our work is to detect patients with CSVD at an early stage, through the evaluation of precocious MRI changes and serum markers of inflammation, to treat untimely risk factors that influence the burden and the worsening of the cerebral disease.

Fusobacterium nucleatum (F. nucleatum) is a common type of bacteria that proliferates in periodontal disease. F. nucleatum can also generate severe generalized inflammation, which is a symptom of many chronic diseases including type 2 diabetes and Alzheimer's disease. The latest research, done in mice, shows that F. nucleatum results in an abnormal proliferation of microglial cells, which are immune cells in the brain that normally remove damaged neurons and infections and help maintain the overall health of the central nervous system. This over-supply of microglial cells also created an increased inflammatory response, the researchers found. Chronic inflammation or infection is believed to be a key determinant in the cognitive decline that occurs as Alzheimer's disease progresses.

Possible links between periodontal disease and Alzheimer's have been posited by scientists in the past. While the new research does not show that F. nucleatum-related periodontal disease leads directly to Alzheimer's disease, the new study suggests that periodontal disease caused by F. nucleatum and left untreated or poorly treated could exacerbate symptoms of Alzheimer's disease. Conversely, treating periodontal disease effectively in those who have early-stage Alzheimer's could potentially slow Alzheimer's progression.

Age-related macular degeneration (AMD) is the leading cause of visual impairment and blindness in people over 65 years old and is the result of damage to the central area of the retina called the macula, which is responsible for reading and driving vision. One major form of early AMD is called drusen, where small yellow cholesterol deposits form in a layer under the retina. They can deprive the retina of blood and oxygen, leading to vision loss. Drusen formation can be slowed by appropriate vitamin supplementation.

The other major form of early AMD is the presence of subretinal drusenoid deposits (SDD), which is lesser known, and requires high-tech retinal imaging to detect. These deposits are also made of fatty lipids and other materials, but form in a different layer beneath the light sensitive retina cells, where they are also associated with vision loss. Currently, there is no known treatment for SDD.

Researchers analyzed 126 patients with AMD and found that patients with cardiovascular disease or stroke were three times more likely to have SDD than patients without. The researchers suggested that the underlying heart and vascular disease likely compromises blood circulation in the eye, leading to the SDDs beneath the retina and ultimately causing vision loss and blindness. "We believe poor ocular circulation that causes SDDs is a manifestation of underlying vascular disease. This study further demonstrates that AMD is not a single condition or an isolated disease, but is often a signal of systemic malfunction which could benefit from targeted medical evaluation in addition to localized eye care."

Neuroinflammation is a hallmark of many neurodegenerative diseases (NDs) and plays a fundamental role in mediating the onset and progression of disease. Microglia, which function as first-line immune guardians of the central nervous system (CNS), are the central drivers of neuroinflammation. Numerous human postmortem studies and in vivo imaging analyses have shown chronically activated microglia in patients with various acute and chronic neuropathological diseases. While microglial activation is a common feature of many NDs, the exact role of microglia in various pathological states is complex and often contradictory. However, there is a consensus that microglia play a biphasic role in pathological conditions, with detrimental and protective phenotypes, and the overall response of microglia and the activation of different phenotypes depends on the nature and duration of the inflammatory insult, as well as the stage of disease development.

This review provides a comprehensive overview of current research on the various microglia phenotypes and inflammatory responses in health, aging, and NDs, with a special emphasis on the heterogeneous phenotypic response of microglia in acute and chronic diseases such as hemorrhagic stroke (HS), Alzheimer's disease (AD), and Parkinson's disease (PD). The primary focus is translational research in preclinical animal models and bulk/single-cell transcriptome studies in human postmortem samples. Additionally, this review covers key microglial receptors and signaling pathways that are potential therapeutic targets to regulate microglial inflammatory responses during aging and in NDs. Additionally, age-, sex-, and species-specific microglial differences will be briefly reviewed.

The T cells found in the human immune system are some of the front-line soldiers in recognizing, attacking, and directing the fight against foreign cells and molecules. They recognize their opponents-from pathogens to cancers-through unique receptors on their surfaces. When a molecule binds to one of these T cell receptors, it activates the T cell, which begins producing a variety of immune molecules. Scientists have long known, however, that this response diminishes over time. When a T cell receptor is activated continuously for weeks or months, the cell gradually produces fewer immune molecules and becomes less effective at destroying a cancer or pathogen.

Researchers long thought that T cell exhaustion might be driven by just a few genes that ended up permanently switched on or off after chronic receptor activation. But in recent years, studies on exhausted T cells began to hint that the cells undergo more major rewiring, with thousands of genes turned on or off. The genes found to be linked to T cell exhaustion helped support this idea; the most critical genes were epigenetic regulators, which remodel the physical structure of DNA to turn on or off hundreds of genes at once. These findings help explain how completely different an exhausted T cell is from other functional T cell states.

The researchers carried out detailed analyses of the epigenetic regulators identified in their screen to understand how they interacted with each other, and homed in on a few particularly important genes. Then, they used CRISPR/Cas9 gene editing to further study the effects of blocking individual genes in T cells that were delivered into living mice. They showed that in mice with tumors, blocking the gene Arid1a led to higher levels of T cells and smaller tumors after just 15 days. Moreover, at a molecular level, the T cells from those mice more closely resembled healthy, persistent immune cells than exhausted, less active T cells.

Do amyloid plaques and tau tangles destine a cognitively intact person to decline? Yes, according to researchers who report that cognitively normal older adults with plaques and tangles declined much faster than those without either pathology - and faster than those with only plaques. Over an average of 3.5 years of follow-up, people with plaques and tangles as measured by PET had a 15 to 20 times higher risk of developing mild cognitive impairment (MCI) or dementia. Other groups analyzing different cohorts appear to be finding the same thing; papers are under review. "This quick progression to MCI is clinically relevant because it tells us that amyloid and tau PET are predictive of imminent cognitive decline. To consider amyloid and tau PET positivity merely as a risk factor, and not manifest disease, may be an underestimation of its malignancy."

Researchers pooled data from 1,325 cognitively intact older adults from seven longitudinal research cohorts and divided them into groups based on their amyloid and tau PET scans: 843 had neither pathology, 328 had only amyloid (A+T-), 55 had amyloid with tau in the medial temporal lobe (A+T+MTL), and 65 had amyloid with tau in the neocortex as well (A+T+Neo). 80 percent of the neocortical-positive participants also had tangles in their MTL, as tau generally spreads from the MTL to the cortex. The researchers tracked scores on the modified preclinical Alzheimer cognitive composite 5 (mPACC5) and Mini-Mental State Exam (MMSE) for an average of 3.5 years after the PET scans. Biomarker-positive participants were an average of seven years older, and had slightly lower baseline MMSE scores, than their biomarker-negative counterparts. While controls held their ground on the mPACC5 and MMSE, A+T- participants slipped a tad and both A+T+ groups declined steeply.

People with plaques and tangles were likelier to develop MCI or dementia. Compared to controls, A+T- volunteers had a 2.5-fold higher risk of developing MCI, while people with A+T+MTL or A+T+Neo had 15 or 19 times higher risk, respectively. Twenty-one people progressed to all-cause dementia; half were A+T+Neo. They were a whopping 40 times likelier to develop dementia in this time frame than controls, while A+T+MTL people had a 5.5-fold higher risk. A+T- volunteers developed dementia at the same rate as controls.

The longevity ecosystem is growing rapidly. But the problem is vast and we're running out of time. The longevity prize encourages novel approaches for turning back our aging clocks. You may be familiar with standard prize models that set a fixed amount to target a specific scientific goal with exact criteria. Those are great! This prize series is different. Its aim is to generate an avalanche of proposals, experiments, and collaborations on undervalued areas. This can include smaller bets growing into larger sums, innovating with novel prize voting mechanisms, or even a series of workshops or hackathons to develop promising ideas. Common to all these prize experiments is their goal to support a growing longevity ecosystem, connecting those who generate proposals for progress with those who want to help execute them, and drive high-trust collaboration toward solving them.

We love to collaborate. The first round of 180k in prizes was fundraised through Gitcoin, supported by community members, whose donations were matched by VitaDAO, Vitalik Buterin, and Stefan George.Thank you for your generous support! If you have an idea for a prize you'd like to sponsor, we'd love to hear from you!

One key problem with the prize model is that academics and biotechs will only perform experiments when they have the money in the bank. That's why our first round of prizes will be given out for hypothesis generation to define the second round of larger prizes. We would like to hear from you: what is the most promising but under-appreciated area of geroscience and longevity biotechnology that we should pursue? Review the literature (and you're welcome to include your own unpublished data), explain why this area is undervalued, generate a hypothesis for making progress, and propose an experiment to further investigate this approach. The more concrete, e.g. including people, resources, and time required for next steps, the better.

Up to 20,000 will be offered in prizes for this round! Finalists will be invited to present their proposal to the judges. Excellent proposals will be moved to the next phase, where they will be eligible for follow-on funding. The prize deadline is the end of 2022.

In murine models, there have been some therapeutic successes reported when aged systems have an influx of stem cells with restored or robust function. One such study showed that ex-vivo treatment of aged muscle stem cells (MuSCs) with a small-molecule inhibitor and a culturing on a porous hydrogel substrate was able to restore potential to the aged MuSCs, and the improved potential was able to impart restored muscle repair when these cells were transplanted into injured, aged muscle. Another exciting study on aged MuSC rejuvenation recently reported that transplantation of aged MuSCs pulsed with transient expression of iPSC reprogramming factors was able to repair injured muscled from aged mice at a rate similar to young MuSCs. These data were also translated in human studies where aged human MuSCs were transiently reprogrammed and transplanted back to the aged donor and showed increased new tissue formation.

On the flip side of these very positive results of improved muscle repair from reprogrammed MuSCs in the aged environment, hematopoietic stem cell (HSC) transplants into aged mice did not have such promising results. In transplants of young, robust HSCs into aged recipient mice, studies report that the aged niche, where the donor stem cells home to in the bone marrow, have negative effects on the robust stem cells populations, altering the cell-intrinsic potential of the transplanted HSCs. Thus, in aged individuals, there may be complex interactions between intrinsic stem cell alterations and the systemic alterations that both need to be addressed for more effective stem cell therapies.

Harnessing the full potential of stem cells could lead to the mitigation of most aging phenotypes but, like most things worthwhile, we need to be patient to develop the most robust effects with these therapies. It will likely require the cooperation between multiple players-whether combinations of stem cell transplants or coordination between stem cell transplants and other pharmacological interventions. However, we may be just at the beginning of understanding these complex interplays.

Cerebral small vessel disease (CSVD) is common among older people. Cognitive impairment is one of the most important manifestations of CSVD. Vascular cognitive impairment and vascular dementia constitute the second most common cause of cognitive impairment. However, the factors causing cognitive impairment remain unknown. White matter lesions (WMLs) and lacunes, which are classical CSVD markers, are related to cognitive impairment in CSVD and could be used to predict cognitive impairment. However, in the clinic, some CSVD patients with mild WMLs have a severe cognitive impairment, which suggests that there are still some important factors that contribute to cognitive impairment in CSVD aside from traditional imaging markers and other imaging markers might enable predictions of cognitive impairment caused by CSVD.

Commonly, cognitive impairment in patients with CSVD occurs due to cerebral hypoperfusion or because other blood components permeate into the brain through a broken blood-brain barrier (BBB). Both of these situations are harmful to neurons and neuroglia. Recently, the glymphatic system was discovered. With the help of Aquaporin 4, cerebrospinal fluid (CSF) flow in the periarterial space enters the brain and becomes interstitial fluid (ISF). It was then drained orderly through the perivenous space, meningeal or olfactory mucosal lymphatics, cervical lymphatic vessel, and finally returned to the peripheral venous. This CSF-ISF exchange system is called the glymphatic system, and its main role includes metabolic product transportation and metabolic waste elimination.

In patients with Alzheimer's disease (AD) and animal models, dysfunction of the glymphatic system contributes to the deposition of amyloid-β and cognitive impairment. CSVD leads to arteriosclerosis and vascular pulsation, which are the driving forces of the glymphatic system. It is difficult to evaluate the glymphatic system in the human body directly. In 2017, based on diffusion tensor imaging (DTI), researchers proposed the DTI analysis along the perivascular space (ALPS) index to evaluate the glymphatic system function. To further explore the reason underlying cognitive impairment in patients with CSVD and identify other new imaging markers of cognitive impairment in patients with CSVD, we studied the relationship of the ALPS index and cognitive impairment in these patients.

We found that the ALPS index was independently linearly correlated with global cognitive function, executive function, attention function, and memory after adjusting for the aforementioned six risk factors or CSVD markers. Our results suggest that glymphatic system impairment is independently related to cognitive impairment in patients with CSVD.