Small‐Vessel Disease and Intracranial Large Artery Disease in Brain MRI Predict Dementia and Acute Coronary Syndrome, Respectively: A Prospective, Observational Study in the Population at High Vascular Risk

Abstract

Background

We aimed to clarify the predictive value of cerebral small‐vessel disease and intracranial large artery disease (LAD) observed in magnetic resonance imaging of the brain and magnetic resonance angiography on future vascular events and cognitive impairment.

Methods and Results

Data were derived from a Japanese cohort with evidence of cerebral vessel disease on magnetic resonance imaging. This study included 862 participants who underwent magnetic resonance angiography after excluding patients with a modified Rankin Scale score >1 and Mini‐Mental State Examination score <24. We evaluated small‐vessel disease such as white matter hyperintensities and lacunes in magnetic resonance imaging and LAD with magnetic resonance angiography. Outcomes were incident stroke, dementia, acute coronary syndrome, and all‐cause death. Over a median follow‐up period of 4.5 years, 54 incident stroke, 39 cases of dementia, and 27 cases of acute coronary syndrome were documented. Both small‐vessel disease (white matter hyperintensities and lacunes) and LAD were associated with stroke; however, only white matter hyperintensities were related to dementia. In contrast, only LAD was associated with acute coronary syndrome. Among the 357 patients with no prior history of stroke, coronary or peripheral artery disease, or atrial fibrillation, white matter hyperintensities emerged as the sole predictor of future stroke and dementia, while LAD was the sole predictor of acute coronary syndrome.

Conclusions

Among cerebral vessels, small‐vessel disease could underlie the cognitive impairment while LAD was associated with coronary artery disease as atherosclerotic vessel disease.

Nonstandard Abbreviations and Acronyms

CDR

clinical dementia rating

LAD

large artery disease

MTA

medial temporal atrophy

SVD

small‐vessel disease

WMH

white matter hyperintensities

Clinical Perspective.

What Is New?

• The predictive value of small‐vessel disease (SVD) and large artery disease (LAD) in magnetic imaging of the brain on incident stroke, dementia, and acute coronary syndrome was investigated in a prospective study in the same population at high vascular risk.

• Both SVD and LAD would predict incident stroke; however, SVD and LAD could predict dementia and acute coronary syndrome, respectively.

• No association between SVD and acute coronary syndrome or between LAD and dementia was observed; this study suggested the associations (1) between SVD and cognitive impairment, and (2) between LAD and coronary heart disease.

What Are the Clinical Implications?

• The presence of SVD and LAD increased the risk of stroke; therefore, strict control of vascular risk factors for stroke prevention will be recommended in patients with SVD or LAD.

• The presence of SVD would increase the risk of incident dementia; therefore, attention and regular checkup for cognitive function will be recommended in patients with SVD.

• The presence of LAD increased the risk of ACS; therefore, regular checkups with ECG and coronary computed tomography angiography will be considered in some cases in patients with LAD.

Recent advances in brain magnetic resonance imaging (MRI) have revealed the presence of asymptomatic small‐vessel disease (SVD) ¹ and intracranial large artery disease (LAD) in healthy individuals. How we should manage those patients with SVD or LAD is an important clinical topic. Because both SVD and LAD are cerebral vessel diseases, their presence increases the risk of stroke. ² , ³ , ⁴ , ⁵ However, it is not sufficient for clinicians to see those patients only for the prevention of stroke. Recent meta‐analysis showed that SVD, particularly white matter hyperintensity (WMH), reflected the risk of not only stroke but also dementia. ² Several studies suggested that LAD increased the risk of coronary artery disease. ⁶ Therefore, we may need to keep in mind not only stroke but also dementia and coronary artery disease in patients with SVD or LAD. However, few prospective studies have examined the association between SVD and coronary artery disease, or that between LAD and dementia. Thus, this study aimed to clarify the predictive values of SVD and LAD for incident stroke, dementia, and acute coronary syndrome (ACS) in patients with vascular risk factors.

METHODS

Data Availability

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Ethics

This study was reviewed and approved by the Institutional Review Board of Tokyo Women's Medical University (approval number 3621), and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki, in accordance with the Ethical Guidelines for Epidemiological Research issued by the Japanese Government and the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. Written informed consent was obtained from all the participants.

Study Design and Patients

Data from 1011 patients were obtained from the Tokyo Women's Medical University Cerebral Vessel Disease (TWMU CVD) registry (URL: https://upload.umin.ac.jp/cgi‐open‐bin/icdr_e/ctr_view.cgi?recptno=R000030620; UMIN000026671). The research protocol and inclusion criteria for the TWMU CVD registry have been previously reported. ⁷ In brief, we consecutively included patients aged ≥40 years who presented with cerebral vessel disease on MRI and 1 or more cerebrovascular risk factors, including arterial hypertension, diabetes, dyslipidemia, chronic kidney disease (CKD), coronary artery disease, atrial fibrillation, or smoking. The exclusion criteria for the registry were any kind of aphasia, evidence of dementia (Clinical Dementia Rating [CDR] ⁸ ≥1), and dependence on activities of daily living and walking because one of the aims of our registry was to determine the factors that influenced incident dementia, cognitive decline, and functional outcome. Each CDR score was derived from interviews conducted with the participants and their collateral sources, individuals familiar with them. Patients who experienced vascular events within 1 month of enrollment were excluded because those patients were at very high risk of recurrent vascular events and their general or neurological conditions also remained unstable. Between October 2015 and July 2019, 1011 outpatients participated in the TWMU CVD study. MRI scans were performed to examine lesions in patients with a history of stroke or suspicious neurological symptoms (eg, headache, vertigo, dizziness, numbness, syncope, or subjective memory impairment). Cognitive screening using the Mini‐Mental State Examination (MMSE) ⁹ was performed at enrollment for most participants. In some cases, these tests were performed within 3 months of enrollment.

To examine the effect of intracranial LAD and incident dementia in independent outpatients, we excluded patients without MR angiography (n=30), those with a modified Rankin Scale score ≥2 (n=60), and MMSE score <24 (n=59) due to suspected previous cognitive impairment. After applying exclusion criteria, 862 patients with complete baseline data were included in the final analyses (Figure 1).

Figure 1. Flowchart of patient recruitment in this study.

MMSE indicates Mini‐Mental State Examination; MRA, magnetic resonance imaging angiography; MRI, magnetic resonance imaging; mRS, modified Rankin scale; and TWMU CVD, Tokyo Women's Medical University Cerebral Vessel Disease.

MRI Protocol and Assessment

Each participant underwent a brain MRI scan within 1 year before entry into the registry. Patients who experience vascular events, cognitive decline, any disease for hospitalization, and surgical therapy after MRI examination were excluded from enrollment. MRI assessments included periventricular hyperintensity, deep WMHs, lacunes, and medial temporal atrophy (MTA). ¹⁰ The WMH severity was visually rated using axial fluid‐attenuated inversion recovery images. Using the Fazekas scale, periventricular hyperintensity and deep WMH were scored on a scale from 0 to 3 (0=none; 1=mild; 2=moderate; and 3=severe). ¹¹ Lesions in the basal ganglia, internal capsule, centrum semiovale, and brainstem with hypointensity on T1‐weighted imaging, hyperintensity on T2‐weighted imaging, and a hyperintense rim around the cavity on fluid‐attenuated inversion recovery were defined as lacunes, ¹ with sizes ranging from 3 to 15 mm. MTA was rated from 0 (absent) to 3 (severe) according to a previous guideline. ¹⁰ The sum of the scores of both sides was used as the MTA grade, which ranged from 0 to 6. For WMH, the lesion was considered significant if PVH Fazekas grade 3 (extending into the deep white matter) or deep WMH Fazekas 2 to 3 (confluent or early confluent) were present. ¹¹ Intracranial arteries were examined, including the intracranial portion of the internal carotid artery, middle cerebral artery (M1 and M2 segments), anterior cerebral artery (A1 and A2), posterior cerebral artery, vertebral artery, and basilar arteries at the time‐of‐flight magnetic resonance imaging angiography as previously reported. ¹² The narrowest diameter of each stenosed vessel was measured and divided by the diameter of the normal vessel proximal to the lesion or distal to the lesion if the proximal artery was diseased. Significant intracranial LAD was defined as a stenosis or occlusion of 50% or greater. The interrater κ for WMH, lacunes, or MTA scores were between 0.80 and 0.85. In cases of disagreement, a third rater (K.K.) was consulted.

Potential Risk Factors

Hypertension was defined as blood pressure ≥140/90 mm Hg on at least 2 measurements or the use of antihypertensive medications. Diabetes was defined as fasting plasma glucose levels ≥126 mg/dL, hemoglobin A1c level ≥6.5%, or administration of antidiabetic therapies. Dyslipidemia was defined as a low‐density lipoprotein cholesterol level ≥140 mg/dL, total cholesterol level ≥220 mg/dL, triglyceride level ≥150 mg/dL, or administration of cholesterol‐lowering therapies. Smoking status was evaluated based on the basis of current smoking habits. Baseline kidney function was determined based on the estimated glomerular filtration rate using the Modification of Diet in Renal Disease formula for Japanese. ¹³

Follow‐Up and Outcomes

The patients were followed up until March 2023. Physical examination findings, treatments, clinical events, and modified Rankin Scale scores were recorded during the follow‐up visits. If the patient could not be followed up, a relative or caregiver was interviewed via telephone. Outcomes were incident stroke, dementia, ACS, and all‐cause death. Stroke and ACS were diagnosed as previously described. ¹⁴ In brief, stroke was clinically defined as a focal neurological deficit as confirmed by MRI or computed tomography. Diagnosis of ACS was defined by standard criteria (compatible clinical history with changes on ECG or in cardiac enzyme concentrations). Those patients often received percutaneous coronary intervention. For each event, the date of the event was used in the time‐to‐event analyses.

Diagnosis of Dementia

Cognitive status was prospectively assessed by a neurologist using the MMSE and CDR. Patients visited outpatient clinics every 3 months to control for their risk factors. Annual data on changes in the patients' general medical conditions were collected through medical records and interviews. Furthermore, cognitive function in everyday life was assessed during each clinical visit to determine the patient's CDR scores. Trained neurologists conducted annual assessments, including medical history, CDR scoring, and neurological examinations. At follow‐up visits, patients were cognitively screened using the MMSE. The final follow‐up data were collected in March 2023. Throughout the follow‐up period, neurologists periodically examined patients for signs of cognitive decline. Clinically significant cognitive impairment was defined as an MMSE score <24 or a decline >1.5 SD from the previous score, as previously reported. ¹⁵ On the MMSE, this corresponded to a decline of >3 points. Additionally, probable dementia was determined when 2 consecutive semiannual CDR scores were >1 and did not revert to normal cognition. To avoid missing incident dementia cases, we continuously monitored participants' medical records, including those from other clinics, to obtain information on the diagnosed dementia. For patients who were unable to visit the clinic, we conducted phone interviews with both the patient and caregiver, whenever possible, to gather clinical data. Finally, an independent committee of neurologists reviewed all potential dementia cases, using all available information to reach a consensus on the diagnosis, according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. ¹⁶ The dementia subtypes were diagnosed according to standardized criteria. ¹⁷ , ¹⁸ The criteria for mixed dementia were met when the investigator considered that the clinical picture presented aspects of both Alzheimer disease dementia and vascular dementia. ¹⁹ The time to dementia was defined as the period between the baseline visit and date of dementia diagnosis. Patients were followed‐up until death or their refusal to continue participating. Patients who did not develop dementia were censored at their final visit.

Statistical Analysis

All analyses were performed using the JMP 14 Pro software (SAS Institute, Cary, NC). Quantitative variables were expressed as medians (interquartile ranges), whereas categorical variables were expressed as frequencies and percentages. Comparisons among 2 groups were performed using Wilcoxon rank‐sum test for quantitative variables and χ² test for qualitative variables. Event rates were estimated using the Kaplan–Meier method, and intergroup differences were assessed using the log‐rank test. For a given outcome, patients who died of causes other than the outcomes were censored at the time of death. Cox proportional hazard regression models were used to evaluate the association of the WMH, lacunes, and intracranial LAD with the risk of stroke, ACS, and dementia by calculating the hazard ratios and 95% CIs. Before we performed Cox proportional regression model, we checked proportional hazards assumption by observing no crossing or plateau of the Kaplan–Meier curves in the 2 groups over time. All variables with P <0.10 in univariate analysis and known related factors (ie, age, sex, education years, hypertension, diabetes, atrial fibrillation, CKD, current smoker, history of stroke or coronary heart disease, and baseline MMSE) were entered for multivariable adjustments. For all analyses, statistical significance was set at P <0.05.

RESULTS

The baseline characteristics of the study participants are summarized in Table 1. A total of 862 patients were included in the study. The median age was 71 years, and 57.5% of the patients were men. Sixty‐six percent of the participants had hypertension, 28% had diabetes, 52% had dyslipidemia, 11% had atrial fibrillation, 46% had CKD, and 48% and 14% had a history of cerebrovascular disease and cardiovascular disease, respectively. The prevalence of moderate or severe WMH, lacunes, and intracranial LAD were 22.9%, 43.7%, and 11.5%, respectively.

Table 1.

Baseline Characteristics

Characteristics	Total (N=862)
Age, median (IQR), y	71 (63–78)
Sex, male, %	57.5
Education, y	14.5 (12–16)
Hypertension, %	65.7
SBP, mm Hg	134 (123–147)
DBP, mm Hg	75 (66–83)
Diabetes, %	28.3
HbA1c, %	6.0 (5.7–6,7)
Dyslipidemia, %	51.5
LDL‐C, mg/dL	105 (86–127)
HDL‐C, mg/dL	60 (49–72)
Triglycerides, mg/dL	109 (78–153)
Atrial fibrillation, %	10.7
Chronic kidney disease, %	46.2
eGFR, mL/min per 1.73 m2	61.2 (50.9–71.4)
Current smoker, %	7.9
Previous stroke/TIA, %	48.3
Previous CAD, %	13.9
Medication, statin use, %	49.7
Cognitive function, MMSE score	28 (26–30)
MRI findings
Presence of moderate or severe WMH, %	22.9
Presence of lacune, %	43.7
Presence of intracranial large artery disease, %	11.5
Medial temporal atrophy (0–6)	2 (2–4)
Indication for the MRI
To follow‐up stroke/TIA, %	48.3
To follow‐up silent brain infarction, %	6.4
To follow‐up WMH, large artery disease, cerebral aneurysm, %	14.4
To examine cause for headache, %	5.5
Cognitive complaints, %	8.9
Vertigo/dizziness/syncope, %	6.4
Numbness/sensory disorders, %	10.2

CAD indicates coronary artery disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c; HDL‐C, high‐density lipoprotein cholesterol; IQR, interquartile range; LDL‐C, low‐density lipoprotein cholesterol; MMSE, Mini‐Mental State Examination; MRI, magnetic resonance imaging; SBP, systolic blood pressure; TIA, transient ischemic attack; and WMH, white matter hyperintensity.

In the initial cohort, 156 patients (18.1%) withdrew consent because of hospital transfer, 47 patients (5.4%) were lost to follow‐up, and 50 patients (5.8%) had died during follow‐up (Figure 1). The mean follow‐up period in all patients was 4.53±1.37 years. During follow‐up, stroke, dementia, and ACS occurred in 54, 39, and 27 patients, respectively. Among the 39 dementia events, 30, 6, and 3 involved Alzheimer disease dementia, vascular dementia, and mixed dementia, respectively. Survival analyses of stroke‐free with respect to WMH, lacunes, and intracranial LAD are shown in Figure 2A. Patients with WMH, lacunes, or intracranial LAD were significantly more likely to have a stroke (P <0.001 for WMH, P=0.010 for lacunes, and P=0.004 for LAD). Survival analyses of dementia‐free patients with WMH, lacunes, and LAD are shown in Figure 2B. Patients with WMH were significantly more likely to have dementia (P<0.001); however, no association was found between lacunes (P=0.557), LAD (P=0.289), or dementia. Survival analyses of ACS‐free patients with respect to WMH, lacunes, and LAD are shown in Figure 2C. Patients with LAD were significantly more likely to have ACS (P<0.001); however, no association was found between WMH (P=0.572) or lacunes (P=0.771), and ACS. Survival analysis of all‐cause death is shown in Figure S1. Patients with lacunes and LAD were significantly more likely to die (P <0.001 both), but the association between WMH and all‐cause death showed borderline significance (P=0.066). The baseline characteristics with reference to incident stroke, dementia, and ACS are shown in Table 2. History of cerebrovascular disease was associated with incident stroke, while age, atrial fibrillation, CKD, baseline MMSE score, and MTA were associated with incident dementia. Diabetes and CKD were both associated with ACS. The Cox proportional multivariate analyses for stroke, dementia, and ACS are shown in Table 3. Using patient groups without severe or moderate WMH, lacunes, or LAD as references, those with severe or moderate WMH and LAD had a significantly elevated risk of stroke after adjusting for confounding factors. The association between lacunes and stroke was borderline significant after adjustment (P=0.098). The association between WMH and dementia was weak and disappeared after adjusting for confounding factors, while the association between LAD and ACS remained significant after adjusting for risk factors.

Figure 2. Kaplan–Meier survival analyses of time to stroke (A), dementia (B), and ACS (C) by the presence of moderate or severe WMH (left panels), lacune (middle panels), and intracranial LAD (right panels) in all patients. ACS indicates acute coronary syndrome; LAD, large artery disease; and WMH, white matter hyperintensity.

 

Table 2.

Baseline Characteristics in Reference to Incident Stroke, Dementia, and Acute Coronary Syndrome

Characteristics	Stroke			Dementia			ACS
	Without stroke (N=808)	With stroke (N=54)	P value	Without dementia (N=823)	With dementia (N=39)	P value	Without ACS (N=844)	With ACS (N=27)	P value
Age, median (IQR), y	71 (63–77)	73 (67–80)	0.07	70 (62–77)	79 (75–83)	<0.001	71 (63–77)	74 (69–79)	0.087
Sex, male %	57.4	59.3	0.792	57.7	53.9	0.633	57.3	66.7	0.33
Education, y	15 (12–16)	14 (12–16)	0.474	14 (12–16)	16 (12–16)	0.517	14 (12–16)	16 (12–16)	0.909
Hypertension, %	64.8	77.8	0.053	65.6	66.7	0.891	65.7	63	0.765
Diabetes, %	27.7	37.7	0.116	28.7	21.1	0.309	27.3	59.3	<0.001
Dyslipidemia, %	50.9	59.3	0.236	52	41	0.182	51.6	48.2	0.726
Chronic kidney disease, %	45.5	55.6	0.153	45.3	64.1	0.022	45.3	74.1	0.003
Atrial fibrillation, %	10.2	17.3	0.108	10.2	21.1	0.033	10.5	14.8	0.476
Current smoker, %	7.6	13	0.157	7.9	7.7	0.955	7.7	15.4	0.153
Previous stroke/TIA, %	46.8	69.8	0.001	48.8	35.9	0.114	48.4	44.4	0.687
Previous CAD, %	13.5	20.4	0.159	14.1	10.3	0.497	13.8	18.5	0.485
Medication, statin use, %	49.4	53.7	0.538	49.8	46.2	0.655	49.7	48.2	0.874
MMSE	28 (26–30)	28 (26–29)	0.206	28 (27–30)	27 (26–28)	<0.001	28 (26–30)	29 (26–30)	0.823
Medial temporal atrophy	2 (2–4)	2 (2–4)	0.21	2 (2–4)	4 (3–4)	<0.001	2 (2–4)	3 (2–4)	0.056

ACS indicates acute coronary syndrome; CAD, coronary artery disease; IQR, interquartile range; MMSE, Mini‐Mental State Examination; and TIA, transient ischemic attack.

Table 3.

Cox Proportional Hazards Regression of White Matter Hyperintensity, Lacune, and Intracranial Large Artery Disease for Stroke, Dementia, and Acute Coronary Syndrome

Total patients	N	Event	Crude HR	P value	Model 1	P value	Model 2	P value
Stroke
WMH 0	665	31	1 (reference)		1 (reference)		1 (reference)
WMH 1	197	23	2.56 (1.48–4.38)	0.001	2.33 (1.32–4.09)	0.004	2.19 (1.21–3.91)	0.01
Lacune 0	485	20	1 (reference)		1 (reference)		1 (reference)
Lacune 1	377	34	2.13 (1.24–3.77)	0.006	2.04 (1.17–3.63)	0.011	1.65 (0.91–3.06)	0.098
LAD0	763	42	1 (reference)		1 (reference)		1 (reference)
LAD1	99	12	2.50 (1.26–4.60)	0.011	2.38 (1.20–4.40)	0.015	2.44 (1.20–4.65)	0.016
Dementia
WMH0	665	21	1 (reference)		1 (reference)		1 (reference)
WMH1	197	18	2.98 (1.57–5.60)	0.001	1.83 (0.95–3.49)	0.07	1.41 (0.69–2.91)	0.349
ACS
LAD 0	763	18	1 (reference)		1 (reference)		1 (reference)
LAD 1	99	9	4.32 (1.84–9.41)	0.001	4.02 (1.71–8.77)	0.002	3.08 (1.27–7.00)	0.014
357 patients with no history of vascular events or atrial fibrillation
Stroke
WMH0	284	6	1 (reference)		1 (reference)		1 (reference)
WMH1	73	5	3.30 (1.01–10.82)	0.049	3.65 (1.05–12.60)	0.041	5.11 (1.32–19.75)	0.018
Dementia
WMH0	284	9	1 (reference)		1 (reference)		1 (reference)
WMH1	73	8	3.56 (1.37–9.23)	0.009	2.18 (0.81–5.82)	0.121	1.26 (0.35–4.51)	0.723
ACS
LAD0	328	9	1 (reference)		1 (reference)		1 (reference)
LAD1	29	3	4.08 (1.10–15.09)	0.035	3.55 (0.95–13.24)	0.059	3.25 (0.83–12.82)	0.092

Model 1: Adjusted for age and sex; Model 2: Adjusted for model 1 and hypertension, diabetes, atrial fibrillation, CKD, previous stroke/TIA and previous CAD for stroke; Adjusted for model 1 and education years, atrial fibrillation, CKD, previous stroke/TIA, MMSE and MTA for dementia; Adjusted for model 1 and diabetes, CKD, current smoker, and previous CAD for ACS. WMH (0: none or mild, 1: PVH Fazekas 3/DWMH Fazekas 2–3, Lacune [0: 0, 1: ≥1]), LAD (0: none or mild, 1: 50% or greater stenosis or occlusion in intracranial large artery). ACS indicates acute coronary syndrome; CAD, coronary artery disease; CKD, chronic kidney disease; DWMH, deep white matter hyperintensity, HR, hazard ratio; LAD, large artery disease; MMSE, Mini‐Mental State Examination; MTA, medial temporal atrophy; PVH, periventricular hyperintensity; TIA, transient ischemic attack; and WMH, white matter hyperintensity.

In 357 patients with no prior history of stroke, coronary or peripheral artery disease, or atrial fibrillation, stroke, dementia, and ACS occurred in 11, 17, and 12 patients, respectively. Survival analyses for stroke‐free (Figure 3A), dementia‐free (Figure 3B), and ACS‐free (Figure 3C) are shown in Figure 3. WMH was associated with stroke (P=0.037) and dementia (P=0.005), while LAD was associated only with ACS (P=0.023). In the COX proportional hazard analysis, those associations were significant in univariate analysis but disappeared after adjusting for age, sex, and confounding factors (Table 3).

Figure 3. Kaplan–Meier survival analyses of time to stroke (A), dementia (B), and ACS (C) by the presence of moderate or severe WMH (left panels), lacune (middle panels), and intracranial LAD (right panels) in 357 patients without any history of stroke and coronary and peripheral artery disease and atrial fibrillation. ACS indicates acute coronary syndrome; LAD, large artery disease; and WMH, white matter hyperintensity.

 

DISCUSSION

This study demonstrated that SVD and intracranial LAD were associated with an increased risk of dementia and ACS, respectively. Although asymptomatic LAD was a clinically neglected risk factor for ACS, this study may attract the attention of physicians to coronary events in asymptomatic patients with LAD.

Previous meta‐analyses have consistently demonstrated that SVD, particularly WMH, increases the risk of incident dementia, ² which aligns with our results. However, no association was found between the intracranial LAD and incident dementia. Few prospective studies have examined this association to date. While vascular contributions have garnered considerable attention as a risk factor for Alzheimer disease dementia, ²⁰ previous cross‐sectional studies have shown an association between intracranial LAD and cognitive impairment or dementia. ²¹ , ²² , ²³ , ²⁴ In a prospective study, Zhu et al revealed that LAD was associated with a heightened risk of progression to dementia in 423 patients with mild cognitive impairment. ²⁵ Additionally, Meng et al showed a relationship between cognitive decline in the LAD and poor collateral circulation. ²⁶ Nevertheless, recent research suggests that amyloid deposition is not associated with cerebral hypoperfusion due to intracranial LAD on positron emission tomography. ²⁷ , ²⁸ As a vascular factor, the involvement of LAD in dementia, particularly Alzheimer disease dementia, appears to be weak.

ACS is a common vascular condition. Coronary artery atheroma is the primary cause of coronary artery disease. Although the Kashima study demonstrated that asymptomatic SVD increases the risk of vascular event, ²⁹ the relationship between SVD and ACS was not shown in this study. The cause of intracranial LAD is also atherosclerotic lesion; therefore, there are several similarities between coronary artery disease and intracranial LAD. ³⁰ Although a modest association has been found between intracranial LAD and coronary artery disease, ³¹ , ³² few studies have examined the risk of LAD in patients with ACS. In this study, the intracranial LAD was associated with both stroke and ACS; however, in asymptomatic individuals, the LAD was associated only with ACS and not with stroke. Given that the risk of incident stroke is very low in asymptomatic stenosis of the middle cerebral artery, ³³ , ³⁴ , ³⁵ asymptomatic LAD may be significantly associated with coronary events rather than incident stroke.

This study has several limitations. First, due to its single‐center setting and a relatively small sample size of patients with vascular risk factors, the generalizability of our results may be limited. Second, we did not measure cerebral hemodynamics in patients with intracranial LAD; therefore, the effect of the LAD on cerebral perfusion remains unclear. Third, only a small number of patients underwent coronary or carotid artery evaluation with computed tomography angiography or carotid ultrasound before enrollment. Last, incident dementia might not be diagnosed before death because 50 patients died during follow‐up compared with 39 incident dementia. However, we believe it was unlikely because we monitored most participants every 3 months for medical management.

In conclusion, both SVD and LAD predicted the risk of stroke. SVD, particularly WMH, was indicative of dementia risk, while intracranial LAD could predict the risk of coronary events. Effective medical management for patients with SVD and LAD should prioritize not only stroke prevention but also the prevention of cognitive decline and coronary events.

Sources of Funding

None.

Disclosures

Dr Kitagawa reports lecture fees from Daiichi‐Sankyo, Kowa, and Kyowa Kirin Pharmaceuticals. The remaining authors have no disclosures to report.

Supporting information

Figure S1