Small Vessels, Big Impact: The Cerebrovascular Condition You Should Watch For

Argye Elizabeth Hillis, MD

According to the World Health Organization, the estimated global prevalence of dementia is currently 50 million, and approximately 15 million strokes occur worldwide each year.^1,2 The incidence of both conditions has increased substantially in recent decades, and further increases are expected as the elderly population continues to expand.³

Ongoing research highlights the significant role of cerebral small vessel disease (CSVD) in the pathogenesis of dementia and stroke, with some findings showing that CSVD accounts for up to 45% and 25% of cases, respectively.⁴ “There is very strong evidence that CSVD, when present, contributes to cognitive decline and dementia. CSVD also results in worse cognitive impairment and slower recovery in people with stroke,” Argye Elizabeth Hillis, MD, professor of neurology, executive vice chair of neurology, and director of the cerebrovascular division at Johns Hopkins University School of Medicine, told NeurologyLive®.

In a study published in 2018 in Stroke, researchers examined links between a CSVD sum score and dementia, stroke, and mortality in 1651 individuals (mean age, 73.3 years; 54.5% women) with no history of stroke or dementia at baseline.⁴ The CSVD sum score ranges from

0 to 4 based on the presence or absence of 4 magnetic resonance imaging (MRI) markers: white matter hyperintensities, lacunae, cere- bral microbleeds (CMs), and perivascular spaces.

After undergoing brain MRI in 2005 through 2011, participants were followed until 2016 and 2017, for a mean follow-up period of 7.2 years. The results showed that a higher CSVD sum score on MRI was associated with an elevated risk of stroke, dementia, and death after adjusting for age, sex, and Framingham Stroke Risk Profile predictors such as coronary heart disease, atrial fibrillation, diabetes, and smoking. For each 1-point increase in the CSVD sum score, the adjusted hazard ratios were 1.54 (95% CI, 1.16-2.03) for stroke, 1.25 (95% CI, 0.95-1.64) for dementia, and 1.15 (95% CI, 1.01-1.31) for mortality, suggesting that the score reflects global vascular brain injury.

CSVD “poses a risk for both cerebrovascular disease and cognitive impairment via effects on arterial stiffness, presenting as microvessel arteriosclerosis with vascular endothelial dysfunction,” Naoki Saji, MD, PhD, and colleagues wrote in a 2016 article.⁵

Underlying Mechanisms

Although the underlying mechanisms are not yet fully understood, it is believed that there is “decreased caliber of the small perforating vessel leading to hypoperfusion and degeneration and death of the myelinated white matter fibers, causing neuronal dysfunction and cell death,” according to May Anne Kim-Tenser, MD, associate professor of clinical neurology at the Keck School of Medicine and medical director of the Neuro Intensive Care Unit at the Keck Medical Center of the University of California.

Some experts have also proposed that damage to the blood—brain barrier and local inflammation may be factors in the pathogenesis of CSVD and its association with stroke and cognitive decline.⁶ “Eventually, there are multiple ischemic events, some with symptoms and some clinically silent,” she said in an interview with NeurologyLive®. Additionally, results of animal research indicate that “even very small infarcts seem to ‘trigger’ or potentiate accumulation of amyloid plaques,” Hillis added.

Other evidence highlights the role of oxidative stress—with the Nox2-NADPH oxidase isoforms implicated as a key mediator—as a “contributor to some of the features of arteriopathy associated with both nonamyloid and amyloid forms of cerebral SVD and its risk factors” including hypertension and as a contributing factor to CSVD-related brain injury and cognitive impairment, according to De Silva and colleagues.⁶

“Other considerations include the ‘hammer effect,’ with long-standing hypertension and lack of aortic distensibility. This may play a role in the genesis of lipohyalinosis or arterial wall stiffening particularly in the large and small vessels, as the distensibility characteristics of the arterial walls are lost between systole and diastole with profound hypertension,” Albert S. Favate, MD, clinical associate professor in the department of neurology, and director of the division of vascular neurology at NYU Langone, told NeurologyLive®.

“This results in stiffening of the aorta, the carotid and vertebral artery system, basilar arteries in the circle of Willis, and that ‘hammer effect’ causes the deposition of a hiatal and light material in the vessel walls. The patient must maintain a high cerebral perfusion pressure in this setting—further placing them at risk for development of small vessel strokes.”

cardiovascular and cerebrovascular diseases, with even mild hypertension showing a connection to CSVD.^3,6,7

In a study published in Hypertension in April 2019, researchers investigated the relationship between hypertension and CSVD lesions in 2460 healthy participants (54% men; mean age, 56 years).³ They found that that both stage 1 (β = .158; 95% CI, 0.046-0.269; P = .006) and stage 2 hypertension (β = .267; 95% CI, 0.171-0.362; P <.001) were closely associated with WMH volumes after adjustment for confounders.

Stage 1 (adjusted odds ratio [aOR], 1.66; 95% CI, 1.00-2.73; P = .048) and stage 2 hypertension (aOR, 1.76; 95% CI, 1.15-2.70; P = .009) were also associated with the presence of lacunae, as well as deep CMs (aOR, 2.50; 95% CI, 1.08-5.79; P = .033) for stage 1 and for stage 2 (aOR, 3.35; 95% CI, 1.61-6.98). An independent association was observed between stage 2 hypertension and moderate to severe enlarged perivascular spaces (aOR, 1.73; 95% CI, 1.36-2.20; P <.001).

There is very strong evidence that CSVD [cerebral small vessel disease], when present, contributes to cognitive decline and dementia. CSVD also results in worse cognitive impairment and slower recovery in people with stroke," said Argyle Elizabeth Hillis, MD.

These findings suggest a dose-response effect of hypertension on the development of CSVD lesions. “Because CSVDs are well-known risk factors for symptomatic stroke or dementia, our findings would indicate that new, stricter [blood pressure] guidelines [per the 2017 American College of Cardiology/American Heart Association recommendations on hypertension] are plausible in terms of preventing diverse CSVDs before symptomatic events,” the authors concluded.

Diabetes, hyperlipidemia, and smoking are additional modifiable factors, whereas other non-modifiable factors aside from age include sex, race, and significant family history. “There are also genetic conditions and diseases that predispose a patient to CVSD, such as CADASIL and Fabry disease,” Kim-Tenser said.

Prevention and Treatment

Clinicians should screen for risk factors, cognitive impairment, and depression, and “eliminate or reduce risk factors and treat depres- sion when present,” Hillis said. An observational study presented at the American Heart Association’s Hypertension 2019 Scientific Sessions showed that patients with high blood pressure had a faster rate of cognitive decline versus those receiving hypertension treatment and those with normal blood pressure.⁸ A similar rate of cognitive decline was observed between patients being treated for high blood pressure and those with normal blood pressure.

Along with close blood pressure and glucose control and treat- ment of elevated non-HDL cholesterol as appropriate, clinicians should encourage patients to quit smoking, engage in daily aerobic exercise, and adhere to a healthy diet low in saturated fats, sugars, and red meat. Hillis also recommends that patients engage in enjoyable, cognitively stimulating activities—such as a book club, music lessons, and classes.

Thomas Hemmen, MD, PhD, vascular neurologist, director of the stroke center, and professor of neurosciences at the University of California, San Diego, said he is “struck by the data showing the need to remain mentally and physically engaged to prevent cognitive decline. Staying active, engaging socially, and maintaining one’s hobbies and interests later in life are very important to reduce dementia progression.”

A longitudinal study described in the November 2019 issue of the American Journal of Geriatric Psychiatry examined links between social engagement and cognitive decline in 217 community-dwelling, cognitively normal adults aged 63 to 89 years.⁹ Participants were assessed at baseline and at 3 years with the Community Healthy Activities Model Program for Seniors questionnaire, the Preclinical Alzheimer Cognitive Composite (PACC), and Pittsburgh compound B-PET to measure amyloid-β (Aβ).

Lower “baseline social engagement was associated with greater amyloid-β—related PACC decline, while higher baseline social engagement was associated with relative preservation of PACC scores (β = .05; P = .03),” the investigators reported. “Low social engagement may be a marker of neurocognitive vulnerability in older adults who are cognitively normal but have evidence of AD [Alzheimer disease] pathophysiologic change.”

Results from a 2019 longitudinal observational study revealed that greater physical activity levels were associated with slower Aβ-related cognitive decline (β = .03; 95% CI, 0.02-0.05; P <.001) and volume loss (β = 482.07; 95% CI, 189.40-774.74; P = .002) in a sample of 182 clinically normal participants from the Harvard Aging Brain Study (mean age, 73.4 years; 56.6% women), even after adjustment for vascular risk.¹⁰ Independent associations were observed between vascular risk and slower Aβ-related PACC decline (β = —0.04; 95% CI, –.06 to –.02; P <.001) and volume loss (β = –483.41; 95% CI, –855.63 to –111.20; P = .01).

“These findings suggest that engaging in physical activity and lowering vascular risk may have additive protective effects on delaying the progression of Alzheimer disease,” the investigators concluded.

Hillis further emphasized the role of adequate sleep in preventing cognitive decline and the importance of screening for sleep problems and referral to specialists if needed, especially when sleep apnea is suspected.^11,12 A systematic review and meta-analysis published in 2017 in JAMA Neurology examined research involving a total of 4,288,419 participants.¹² The pooled results of 6 prospective studies demonstrated a 26% greater risk (risk ratio, 1.26; 95% CI, 1.05-1.50) of developing cognitive impairment among individuals with sleep-disordered breathing.

Favate added that “obstructive sleep apnea can cause hypertension, and effective sleep management with a CPAP device will also reduce the patient’s blood pressure and stroke risk.”¹³

When describing the connection between CSVD and aging and dementia, Hemmen recommended that clinicians focus on brain health and the “Life’s Simple 7” from the American Heart Association.^14,15 These include many of the previously mentioned strategies to improve cere-brovascular health, such as blood pressure and glucose control as well as lifestyle modifications. “Many clinical providers do not fully value the magnitude of benefit these simple prevention strategies can have,” he said in an interview with NeurologyLive®.

“Once CSVD is discovered, aggressive treatment of modifiable risk factors is essential,” Kim-Tenser said. “One of the biggest challenges with these patients is that much of the early damage is clinically silent and is only discovered when a patient has a larger stroke or on scans for evaluation of other diseases. It is often discovered at later stages, which may make treatment more difficult.”

Future Directions

Multiple studies are currently investigating advanced imaging techniques that would enable identification of mild CSVD to allow for early aggressive treatment. Other ongoing trials are focusing on the development of “new substances and medications to treat the underlying risk factors and prevent progression of CVSD, as well as neuroprotectant medications to slow or prevent neuronal cell death,” Kim-Tenser said. “There are also studies evaluating substances to treat genetic conditions, such as enzyme replacement therapy in Fabry disease.”

Hillis added that there is a need for research exploring potential interventions to reverse CSVD pathology, such as demyelination of white matter tracts, while Hemmen cited the need to elucidate the etiology of white matter disease and pointed to a review by Joanna Wardlaw that discussed the lack of understanding in this area.¹⁶ “We know the correlations with diabetes, high blood pressure, and inac- tivity, but better understanding of the actual mechanisms may better help to prevent the condition,” he said.

Favate noted that one particularly worthy focus is the connection between cerebrovascular ischemic disease and activation of the APOE allele. “In addition to the presence of small vessel infarcts and large vessel infarcts causing decline due to neuronal loss, there is a further consideration that in many cases, the production of neuro-fibrillary tangles and amyloid deposition may be accelerated in the setting of multi-infarct state whether it is small or large vessel disease,” he said.

“Studies investigating interventions in this area to promote the downregulation of the production of neurofibrillary tangles, tau, and even amyloid is, in my opinion, an important area for future research and intervention.”

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