Small Vessel Disease Burden Predicts Incident Dementia and Poor Functional Outcome in Independent Outpatients

Abstract

Background:

Total small vessel disease (SVD) score is used to measure the burden of SVD.

Objective:

This study aimed to clarify the predictive value of total SVD score for incident dementia and functional outcomes in independent outpatients with vascular risk factors.

Methods:

We derived data from a Japanese cohort in which patients underwent magnetic resonance imaging and cognitive examinations. They were followed up until March 2023. The primary outcomes was dementia. Secondary outcome was functional outcomes. We measured a modified Rankin scale (mRS) score at the last visit and defined poor functional outcomes as mRS score ≥3.

Results:

After excluding those with a mRS score ≥2, Mini-Mental State Examination score in Japanese version < 24, and missing T2* images, 692 patients were included. During a median follow-up period of 4.6 years, dementia occurred in 31 patients. In multivariate analysis, the score 4 group showed a significantly higher risk of incident dementia than the score 0–3 groups (adjusted hazard ratio, 6.25; 95% CI, 1.83–21.40, p = 0.003). The total SVD score was also independently related to poor functional outcome.

Conclusions:

The total SVD score of 4, and ≥1 could predict dementia and poor functional outcomes, respectively. Our results suggest intensive management of patients with SVD to prevent dementia and to maintain independent activities of daily living.

Keywords

Alzheimer’s disease dementia functional outcome small vessel disease score

INTRODUCTION

Cerebral small vessel disease (SVD) is a disorder of the cerebral microvessels that includes both symptomatic and asymptomatic abnormalities. SVD is a manifestation of endothelial dysfunction, blood-brain barrier dysfunction, impaired vasodilation, impaired blood flow and interstitial fluid drainage, and vessel stiffening. 1 Symptomatic SVD includes lacuna syndrome, intracerebral hemorrhage, and vascular dementia. Advances in magnetic resonance imaging (MRI) have revealed the presence of asymptomatic SVD, including recent small subcortical infarct, white matter hyperintensity (WMH), lacune, cerebral microbleed (CMB), enlarged perivascular space (EPVS), cortical superficial siderosis, brain atrophy, and cortical cerebral microinfarct. 2 Recently, a total SVD score was proposed to evaluate the overall SVD burden by incorporating four established neuroimaging markers of SVD; WMH, lacunes, CMB, and EPVS. 3 Although the total SVD score is a simple grading scale ranging from 0 to 4, it is associated with age, vascular risk factors and lacunar stroke.3,4, 3,4 In a population study, the total SVD score was associated with incident stroke, 5 but was only weakly associated with dementia.5,6, 5,6 Furthermore, it remains unknown whether the association between total SVD score and dementia is independent of brain atrophy such as medial temporal atrophy, a strong predictor for Alzheimer’s disease. 7

The total SVD score is related to survival in both patients with stroke and the general population,5,8,9 , 5,8,9 and previously, several reports have shown that total SVD scores were related to functional outcomes at 90 days after onset in patients with acute ischemic10 - 12 and hemorrhagic stroke.13,14, 13,14 However, whether total SVD scores predict long-term clinical outcomes in outpatients with vascular risk factors remains unclear. This study aimed to examine the predictive value of the total SVD burden on dementia and functional outcome in independent outpatients with vascular risk factors.

METHODS

Study design and patients

Data were derived from a prospective study, the Tokyo Women’s Medical University Cerebral Vessel Disease (TWMU CVD) registry (Registration URL: https://www.umin.ac.jp/ctr/index.htm; UMIN000026671). Written informed consent was obtained from all the participants. This study was approved by the Institutional Review Board of Tokyo Women’s Medical University (approval number 3621). The research protocol and inclusion criteria for the TWMU CVD registry have been described in detail previously. 15 Briefly, we consecutively included patients aged > 40 years who presented with cerebral vessel disease on MRI and one or more cerebrovascular risk factors such as arterial hypertension, diabetes mellitus, 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]≥1), 16 and dependence on activities of daily living and walking. Each CDR score was based on interviews with the participants and someone familiar with the participants who served as a collateral source. We excluded patients who experienced vascular events within 1 month of enrollment. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki, in line with the Ethical Guidelines for Epidemiological Research by the Japanese Government and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Between October 2015 and July 2019, 1,011 outpatients were enrolled in the TWMU CVD study. MRI was generally performed to examine lesions in patients with a history of stroke or suspicious neurological symptoms (e.g., headache, vertigo, dizziness, numbness, syncope, or subjective memory impairment). The Mini-Mental State Examination in Japanese version (MMSE-J) was used to screen for suspected cases of cognitive decline. MMSE-J is widely used for cognitive examination in Japan.17,18, 17,18 Participants also received Japanese version of the Montreal Cognitive Assessment (MoCA-J) 19 whenever possible. Cognitive tests were performed at enrollment in most cases; however, in some cases, these tests were performed within 3 months of enrollment.

To examine functional outcomes, incident dementia and the effect of total SVD scores, we excluded patients without T2* imaging results (n = 191) and those with a modified Rankin Scale (mRS) score ≥2 (n = 61) and MMSE-J score < 24 (n = 67) owing to suspected previous cognitive impairment. Finally, all analyses were based on 692 patients with complete baseline data (Fig. 1).

Fig. 1

Flowchart of patient recruitment in this study. mRS, modified Rankin scale; MMSE-J, Mini-Mental State Examination in Japanese version; TWMU CVD, Tokyo Women’s Medical University Cerebral Vessel Disease; SVD, small vessel disease.

MRI protocol and assessment

Each participant underwent a brain MRI scan within 1 year of entry into the registry. All participants were scanned using a 1.5T MRI scanner (Philips Ingenia 1.5T, Siemens Magnetom Avanto fit 1.5T). MRI assessments included WMHs consisting of periventricular hyperintensity (PVH) and deep WMHs, lacunar infarctions (LI), CMBs, EPVS, total SVD score, 3 and medial temporal atrophy (MTA). 20 The severity of the WMH was visually rated using axial fluid-attenuated inversion recovery (FLAIR) images. Based on the Fazekas scale (0 = none; 1 = mild; 2 = moderate; 3 = severe), 21 PVH and DWMH were scored from 0 to 3. 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 FLAIR were defined as LI 2 ; the sizes of which ranged from 3 to 15 mm. CMBs were defined as punctate or small patchy lesions < 10 mm in diameter with low intensity on T2*-weighted imaging. 2 EPVSs were defined as round, oval, or linear-shaped lesions with a smooth margin and signal intensity equal to that of the cerebrospinal fluid on both T1 and T2-weighted images. 2 We counted the EPVS on the basal ganglia slide with the highest number of lesions. MTA was rated from 0 (absent) to 3 (severe) according to a previous guideline. 20 The sum of scores of both sides was used as MTA grade, ranging from 0 to 6. The total SVD score was assigned from 0 to 4 by incorporating all four MRI markers; WMH, LI, CMB, and EPVS. 3 One point was awarded for WMH if PVH Fazekas 3 (extending into the deep white matter) and /or DWMH Fazekas 2–3 (confluent or early confluent) were present. For LI, one point was awarded if ≥1 asymptomatic lesions were present. For CMB, one point was awarded if ≥1 CMB was present in the basal ganglia, thalamus, internal or external capsule, white matter, cortico-subcortical junction, cerebellum, or brainstem. For EPVS, one point was awarded if > 10 EPVS were present in the slice, including the basal ganglia. All grades of SVD-related findings were rated by two trained board-certified neurologists (M.H. and M.S.) who were blinded to the clinical details. The interrater κ for each SVD feature or MTA score was between 0.80 and 0.85. A third rater (K.K.) was consulted in cases of disagreement.

Follow-up and outcomes

The patients were followed up until March 2023. Physical examination findings, treatments, clinical events, and mRS scores were recorded during follow-up visits. A relative or caregiver was interviewed via telephone if the patient could not be followed up. The primary outcome was incident dementia. Diagnosis of incident dementia was described in our recent study. 18 In brief, cognitive status was prospectively assessed by a neurologist using the MMSE-J and CDR. Patients visited outpatient clinics to control for risk factors every 3 months to prevent stroke. Annual evaluations were performed by trained neurologists and included medical history, CDR score determination, and neurological examinations. The final follow-up data were collected on March 2023. During the follow-up period, patients with suspected cognitive decline were periodically examined using Clinical Dementia Rating-Japanese version, which was translated from “Current version and scoring rules: The clinical dementia rating (CDR)” by Morris et al. (1993). 19 Patients were considered to have probable dementia if they had two consecutive semiannual CDR scores ≥1 and did not revert to normal cognition. In this case, we determined the date of dementia when patients firstly showed CDR scores ≥1. For patients who could not visit the clinic, a phone interview to collect clinical data was conducted with the patient and caregiver, whenever possible. Finally, an independent committee of neurologists reviewed all potential cases of dementia with all available information to reach a consensus on the diagnosis, according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). 22 The dementia subtypes were diagnosed according to standardized criteria.23,24, 23,24 The criteria for mixed dementia were met when the investigator considered that the clinical picture presented aspects of both Alzheimer’s disease dementia and vascular dementia. 25 The secondary outcome was functional outcomes. We measured the mRS score at the last visit and defined poor functional outcomes as the mRS score ≥3.

Statistical analyses

All analyses were performed using JMP 14 Pro (SAS Institute, Cary, NC, USA). Quantitative variables were expressed as means±SD or medians (interquartile ranges [IQR]) for normally and non-normally distributed data, respectively, whereas categorical variables are expressed as frequencies and percentages. Comparisons among multiple groups were performed using one-way analysis of variance or the Kruskal– Wallis test for quantitative variables and the χ 2 test for qualitative variables, as appropriate. 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 total SVD score with the risk of dementia by calculating the hazard ratios and 95% confidence intervals (CIs). All variables with p < 0.10 in univariate analysis (i.e., age, sex, hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, chronic kidney disease, previous cerebrovascular disease, baseline MMSE-J, MTA) for incident dementia and total SVD scores were entered for multivariable adjustments. We also evaluated the association of each SVD feature in order to compare our findings with the previous findings. 26 We performed a multiple logistic regression analysis with adjustments for age, sex, hypertension, diabetes mellitus, atrial fibrillation, chronic kidney disease, current smoker, previous cerebrovascular and cardiovascular disease, follow-up time to identify the predictors of poor functional outcomes, defined as an mRS score ≥3 at the final visit. 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 692 patients were included in the study. The median age was 71 years, and 57.7% of the patients were men. Sixty-seven percent of the participants had hypertension, 29% had diabetes mellitus, 51% had dyslipidemia, 11% had atrial fibrillation, 47 % had CKD, and 50% and 15 % had a history of cerebrovascular disease and cardiovascular disease, respectively. The prevalence of severe WMH, LI, CMB, and EPVS > 10 in the basal ganglia slice was 23.8%, 44.8%, 33.8%, and 9.2%, respectively. The total SVD score 0, 1, 2, 3, and 4 were 258 (37.3%), 199 (28.8%), 144 (20.8%), 70 (10.1%), and 21 (3.0%), respectively. The median total SVD score was 1 (0–2). The median MMSE-J score was 28 (26–30). Among 692 patients, 679 also received MoCA-J test. There was no significant difference in baseline information and MMSE-J between those with and without MoCA-J test except for a percentage of history of cerebrovascular disease (Supplementary Table 1).

Table 1

Baseline characteristics of patients (N = 692)

Characteristics	Values or frequency
Age, median (IQR), y	71 (63-78)
Sex, male, %	58.8
Education, y	15 (12-16)
Hypertension, %	67.4
Systolic blood pressure, mmHg	134 (123-147)
Diastolic blood pressure, mmHg	75 (66-83)
Diabetes mellitus, %	29.0
HbA1c, %	6.0 (5.7-6.7)
Dyslipidemia, %	50.7
LDL-C, mg/dL	105 (86-126)
HDL-C, mg/dL	60 (49-72)
Triglyceride, mg/dL	109 (79-153)
Atrial fibrillation, %	11.1
Chronic kidney disease*, %	46.8
eGFR, ml/min/1.73 m²	60.9 (50.7-71.3)
Cigarette smoking, Current smoker, n (%)	7.4
Previous cerebrovascular disease, %	52.2
Previous cardiovascular disease, %	13.3
Global cognitive function, MMSE-J score	28 (26-30)
MRI findings
Presence of moderate or severe WMH, %	24.3
Presence of lacune, %	45.7
Presence of microbleeds, %	33.7
Presence of EPVS (>10), %	9.5
Medial Temporal lobe atrophy (0-6)	2 (2-4)
Total SVD score (0-4)	1 (0-2)
Score 0, %	37.3
1, %	28.8
2, %	20.8
3, %	10.1
4, %	3.0

DWMH, deep white matter hyperintensity; EPVS, enlarged perivascular space; eGFR, an estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MMSE-J, Mini-Mental State Examination in Japanese version; PVH, periventricular hyperintensity; SVD, small vessel disease; WMH, white matter hyperintensity *Chronic kidney disease was defined as eGFR of less than 60 ml per minute per 1.73 m² of body-surface area.

In the initial cohort, 112 patients (16.2%) withdrew consent owing to hospital transfer, 52 patients (7.5%) were lost to follow-up, and 45 patients (6.5%) had died during follow-up (Fig. 1). 69.8% (n = 483) of the patients were examined in a clinic at the end of follow-up. 10.0% (n = 69) of the patients were assessed by phone call. Mean follow-up period in all patients and in the SVD score 0, score 1, score 2, score 3, and score 4 groups were 4.48±1.40 and 4.35±1.33, 4.52±1.37, 4.66±1.51, 4.52±1.48 and 4.49±1.52 years, respectively. No difference in the follow-up period were observed among the five total SVD score groups. The association between the total SVD score and baseline factors is shown in Supplementary Table 2. Higher SVD scores were associated with age, male sex, hypertension, CKD, a history of cerebrovascular disease, low MMSE-J scores, and medial temporal atrophy.

Event risk

During the follow-up, dementia occurred in 31 patients. Among the 31 dementia events, 23, six, and two involved Alzheimer’s disease dementia, vascular dementia, and mixed dementia, respectively. Survival analyses for dementia-free patients in the total SVD score groups are shown in Fig. 2. Patients with higher total SVD scores were significantly more likely to progress to dementia (p = 0.010) than those with lower total SVD scores. Each SVD category for the risk of dementia in the Kaplan-Meier survival analyses are shown in Supplementary Figure 1. In each SVD category, WMH was associated with incident dementia, but neither lacune nor CMB was related to dementia. EPVS showed borderline significance (p = 0.091). The baseline characteristics with reference to incident dementia and poor functional outcome are shown in Table 2. Age, baseline MMSE-J score, and MTA were associated with incident dementia. Age, hypertension, diabetes mellitus, atrial fibrillation, CKD, and a history of cerebrovascular and cardiovascular disease, MMSE-J score, and MTA were associated with poor functional outcomes (mRS score ≧ 3). Cox multivariate analyses for dementia among all total SVD score groups are shown in Table 3. Using the score 0 group as a reference, the score 4 group had a significantly high risk of incident dementia. In multivariate analyses, the score 4 group showed a significantly higher risk of incident dementia than the score 0–3 groups, which was used as a reference after adjusting for age, sex, hypertension, diabetes mellitus, dyslipidemia, CKD, previous stroke, baseline MMSE-J score, and MTA (adjusted hazard ratio, 6.25 (1.83–21.40); p = 0.003). Cox multivariate analyses for dementia in each SVD category are shown in Supplementary Table 3. Significance of WMH for incident dementia in crude analysis disappeared after adjusting for age and sex.

Table 2

Baseline characteristics in reference to incident dementia and poor functional outcome

	Dementia			Functional outcome
	Without dementia	With dementia	p	Fair: mRS 0-2	Poor: mRS 3-6	p
	(N = 661)	(N = 31)		(N = 598)	(N = 94)
Age, median (IQR), y	70 (62-77)	79 (75-84)	< 0.001	70 (62-76)	76 (70-82)	< 0.001
Sex, male %	59	54.8	0.645	58	63.8	0.288
Education, y	16 (12-16)	14 (12-16)	0.146	16 (12-16)	15 (12-16)	0.191
Hypertension, %	54.8	68	0.127	64.9	83	< 0.001
Diabetes mellitus, %	29.5	20	0.265	27.5	38.7	0.027
Dyslipidemia, %	51.1	41.9	0.316	50.5	52.1	0.771
Atrial fibrillation, %	10.7	20	0.112	9.8	19.4	0.006
Chronic kidney disease, %	46.1	61.3	0.099	43.8	65.9	< 0.001
Current smoker, %	7.4	9.7	0.63	8.1	3.2	0.095
Previous cerebrovascular disease, %	52.6	45.2	0.419	50.6	62.8	0.028
Previous cardiovascular disease, %	13.2	16.1	0.637	12.1	21.3	0.015
MMSE-J	28 (26-30)	28 (25-28)	< 0.001	28 (27-30)	27 (26-29)	< 0.001
MTA	2 (2-4)	4 (2-4)	< 0.001	2 (2-4)	4 (2-4)	< 0.001

MMSE-J, Mini-Mental State Examination in Japanese version; MTA, medial temporal atrophy.

Table 3

Cox proportional hazards regression of total SVD score for dementia

					Model 1		Model 2
Total SVD score	N Participants	N Events	Crude HR (95% CI)	p	Adjusted HR (95% CI)	p	Adjusted HR (95% CI)	p
0	258	7	1 (reference)		1 (reference)		1 (reference)
1	199	10	1.71 (0.65-4.50)	0.272	1.40 (0.50-3.90)	0.512	1.93 (0.72-5.22)	0.194
2	144	7	1.55 (0.54-4.42)	0.418	0.98 (0.32-2.98)	0.975	1.06 (0.34-3.27)	0.914
3	70	3	1.45 (0.37-5.62)	0.601	0.80 (0.20-3.23)	0.756	0.62 (0.12-3.17)	0.566
4	21	4	7.40 (2.15-25.48)	0.006	3.93 (1.07-14.37)	0.055	7.01 (1.68-29.31)	0.008
Score 0-3	671	27	1 (reference)		1 (reference)		1 (reference)
Score 4	21	4	4.95 (1.46-12.66)	0.014	3.76 (1.24-11.38)	0.046	6.25 (1.83-21.40)	0.003

Model 1: adjusted for age, sex; model 2: adjusted for model 1 and hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease, baseline MMSE-J, medial temporal atrophy. MMSE-J, Mini-Mental State Examination in Japanese version; CI, confidence interval; HR, hazard ratio; N, number of participants; n, number of incident dementia.

Fig. 2

Kaplan Meier survival analyses of time to dementia by the total small vessel disease (SVD) score.

Functional prognosis

Figure 3 shows the mRS score distribution for each total SVD score group at the last visit. In the univariate logistic regression analysis (Table 4), the score 0 group had significantly fewer patients with poor outcomes (mRS ≥3) than the score 1, 2, 3, and 4 groups (5.8% versus 15.6%, 15.2%, 25.7%, and 33.3%, respectively). In the multivariate logistic regression analysis (Table 4), after adjusting for age, sex, history of hypertension, diabetes, CKD, atrial fibrillation, previous stroke, and coronary artery disease, score 1, 2, 3, and 4 groups still showed a higher risk of poor functional outcomes than the score 0 group, which was used as a reference (the score 1 group: odds ratio [OR], 2.64; 95% CI, 1.32–5.29; p = 0.006; the score 2 group: OR, 2.21; 95% CI, 1.04–4.68; p = 0.039; the score 3 group: OR, 3.27; 95% CI, 1.42–7.52; p = 0.005; the score 4 group: OR, 5.01; 95% CI, 1.61–15.63; p = 0.006). The mRS score distribution for each SVD category (WMH, lacunes, CMB, and EPVS), suggesting that each SVD category was associated with poor functional outcomes is shown in Supplementary Figure 2. In the multivariate logistic regression analysis (Supplementary Table 4), after adjusting for age, sex, and confounding factors (history of hypertension, diabetes, CKD, atrial fibrillation, previous stroke, and coronary artery disease, MMSE-J, MTA, and follow-up time), WMH, lacunes, and EPVS still showed a significantly high risk of poor functional outcomes.

Fig. 3

Distribution of mRS score at the last visit in all patients according to the total small vessel disease (SVD) score. The percentages of participants with mRS scores obtained at the last visit are shown for each cell. mRS, modified Rankin scale.

Table 4

Multivariate logistic regression of total SVD score for poor functional outcome (modified RS≥3)

					Model 1		Model 2
	N Participants	N Events	Crude OR (95% CI)	p	Adjusted OR (95% CI)	p	Adjusted OR (95% CI)	p
Total SVD score
0	258	15	1.00 (reference)		1.00 (reference)		1.00 (reference)
1	199	32	3.01 (1.57-5.74)	< 0.001	2.69 (1.39-5.19)	0.003	2.64 (1.32-5.29)	0.006
2	144	22	2.92 (1.46-5.83)	0.002	2.42 (1.20-4.89)	0.014	2.21 (1.04-4.68)	0.039
3	70	18	5.61 (2.65-11.85)	< 0.001	4.46 (2.08-9.59)	< 0.001	3.27 (1.42-7.52)	0.005
4	21	7	8.10 (2.84-23.07)	< 0.001	4.91(1.67-14.44)	0.004	5.01 (1.61-15.63)	0.006

Model 1: adjusted for age, sex; model 2: adjusted for model 1 and history of hypertension, diabetes, CKD, AF, previous stroke, previous history of coronary artery disease, baseline MMSE-J, medial temporal atrophy, and follow-up time. MMSE-J, Mini-Mental State Examination in Japanese version; CI, confidence interval; OR, odds ratio; N, number of participants; n, number of poor functional outcome.

DISCUSSION

First, this study showed that the total SVD score was associated with incident dementia independent of risk factors, MMSE-J and medial temporal atrophy in independent outpatients.

This study showed a high cutoff value of total SVD scores (score 4) for the risk prediction of dementia, in line with a previous study showing that the score 3 or 4 groups had a high risk of incident dementia.5,6, 5,6 A combination of several SVD categories would be necessary to determine the risk of incident dementia. Among the SVD categories, only WMH was associated with dementia. Close association between WMH and incident dementia is consistent with that of a previous systematic meta-analysis. 26 Linear association was reported between total SVD score and cognitive function27,28, 27,28 or cognitive decline,6,29, 6,29 suggesting that not only the presence of WMH but also accumulation of other SVD category is an important determinant for incident dementia.

The relationship between total SVD scores and long-term functional outcomes in independent outpatients has not been evaluated previously; however, total SVD scores in patients with acute ischemic and hemorrhagic stroke10 - 14 have been shown to predict poor functional outcomes evaluated using the mRS at 3 months after onset. In addition, previous studies have shown that cerebral SVD, especially WMH, is associated with dysphagia,30,31, 30,31 gait disturbance, 32 and parkinsonism. 33 Moreover, Su et al. showed that total SVD scores were associated with stroke-associated pneumonia in acute cardioembolic stroke. 34 Therefore, long-term outcomes in patients with cerebral SVD could be influenced by vascular events, cognitive decline, motor disturbance and swallowing problem.

This study had several limitations. First, because of the single-center setting with a relatively small sample size of patients with vascular risk factors, our results may not be generalizable. The small number of events with many covariates would also make our analysis underpowered. Second, the functional outcome was evaluated at the last visit; thus, the follow-up period may have differed among individuals. However, the mean follow-up period was approximately 4.5 years and similar among all the SVD groups. Third, 24% of the patients withdrew consent or were lost to follow-up; thus, the follow-up was incomplete. Fourth, functional outcome was evaluated using mRS score alone in this study. mRS was developed to assess functional decline after stroke, however, the scale was also used to assess global disability in Parkinson’s disease 35 and normal pressure hydrocephalus with Alzheimer’s disease pathology. 36 The addition of other functional outcome index such as the Amsterdam Instrumental Activities of Daily Living (A-IADL) questionnaire 37 was preferable. Fifth, brain atrophy was evaluated with grading scale of medial temporal atrophy in this study, however, addition of volumetric assessment for general brain atrophy was preferable.

Conclusions

Total SVD score of 4 predicted dementia, and total SVD scores of ≧ 1 increased risk of poor functional outcomes, independent of vascular risks and confounding factors. Our results suggest intensive medical control of patients with SVD to prevent cognitive impairment and to maintain independent activities of daily living. Further multicenter studies with large sample sizes are warranted.

AUTHOR CONTRIBUTIONS

Kazuo Kitagawa (Conceptualization; Data curation; Formal analysis; Investigation; Resources; Validation; Writing – original draft; Writing – review & editing); Sono Toi (Data curation); Megumi Hosoya (Data curation); Misa Seki (Data curation); Sae Yamagishi (Data curation); Takao Hoshino (Supervision); Hiroshi Yoshizawa (Supervision).

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgments to report.

FUNDING

This study was supported in part by Research Funding of Longevity Sciences (28-15, 30-1) from the National Center for Geriartrics and Gerontology, the Japan.

CONFLICT OF INTEREST

Dr. Kitagawa received personal fee from Kyowa Kirin and Kowa, grants and personal fees from Daiichi Sankyo, and grants from Bayer and Dainihon Sumitomo outside the submitted work. Other authors have no conflicts of interest to disclose.

DATA AVAILABILITY

The data analyzed during this study are available from the corresponding author on reasonable request.

The supplementary material is available in the electronic version of this article: .

References

Wardlaw

, Smith

, Dichgans

. Small vessel disease: mechanisms and clinical implications. Lancet Neurol 2019; 18: 684–696.

Duering

, Biessels

, Brodtmann

, et al. Neuroimaging standards for research into small vessel disease-advances since 2013. Lancet Neurol 2023; 22: 602–618.

Staals

, Makin

, Doubal

, et al. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Neurology 2014; 83: 1228–1234.

Yakushiji

, Charidimou

, Noguchi

, et al. Total small vessel disease score in neurologically healthy Japanese adults in the Kashima Scan Study. Intern Med 2018; 57: 189–196.

Yilmaz

, Ikram

, Niessen

, et al. Practical small vessel disease score relates to stroke, dementia, and death. Stroke 2018; 49: 2857–2865.

Jiang

, Wang

, Yuan

, et al. Total cerebral small vessel disease burden is related to worse performance on the Mini-Mental State Examination and incident dementia: a prospective 5-year follow-up. J Alzheimers Dis 2019; 69: 253–262.

Frisoni

, Fox

, Jack

Jr , et al. The clinical use of structural MRI in Alzheimer disease. Nat Rev Neurol 2010; 6: 67–77.

Song

, Kim

, Song

, et al. Total cerebral small-vessel disease score is associated with mortality during follow-up after acute ischemic stroke. J Clin Neurol 2017; 13: 187–195.

Del Brutto

, Mera

, Recalde

, et al. Total cerebral small vessel disease score and all-cause mortality in older adults of Amerindian ancestry: The Atahualpa Project. Eur Stroke J 2021; 6: 412–419.

10.

Huo

, Li

, Zhang

, et al. Total small vessel disease burden predicts functional outcome in patients with acute ischemic stroke. Front Neurol 2019; 10: 808.

11.

Ryu

, Jeong

and Kim

. Total small vessel disease burden and functional outcome in patients with ischemic stroke. PLoS One 2020; 15: e0242319.

12.

, Khlif

, Lemmens

, et al. Imaging markers of brain frailty and outcome in patients with acute ischemic stroke. Stroke 2021; 52: 1004–1011.

13.

Lioutas

, Wu

, Norton

, et al. Cerebral small vessel disease burden and functional and radiographic outcomes in intracerebral hemorrhage. J Neurol 2018; 265: 2803–2814.

14.

Kimura

, Miwa

, Takasugi

, et al. Total small vessel disease score and functional outcomes following acute intracerebral hemorrhage. J Stroke Cerebrovasc Dis 2020; 29: 105001.

15.

Kubota

, Iijima

, Shirai

, et al. Association between cerebral small vessel disease and central motor conduction time in patients with vascular risk. J Stroke Cerebrovasc Dis 2019; 28: 2343–2350.

16.

Morris

. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 1993; 43: 2412–2414.

17.

Futamura

, Hieda

, Mori

, et al. Toxic amyloid-β42 conformer may accelerate the onset of Alzheimer’s disease in the preclinical stage. J Alzheimers Dis 2021; 80: 639–646.

18.

Adachi

, Toi

, Hosoya

, et al. Association of age-related spontaneous internal jugular vein reflux with cognitive impairment and incident dementia. J Alzheimers Dis 2023; 96: 1221–1230.

19.

Fujiwara

, Suzuki

, Yasunaga

, et al. Brief screening tool for mild cognitive impairment in older Japanese: validation of the Japanese version of the Montreal Cognitive Assessment. Geriatr Gerontol Int 2010; 10: 225–232.

20.

Kim

, Kim

, Choi

, et al. T1-weighted axial visual rating scale for an assessment of medial temporal atrophy in Alzheimer’s disease. J Alzheimers Dis 2014; 41: 169–178.

21.

Fazekas

, Chawluk

, Alavi

, et al. MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. AJR Am J Roentgenol 1987; 149: 351–356.

22.

Regier

, Kuhl

and Kupfer

. The DSM- Classification and criteria changes. World Psychiatry 2013; 12: 92–98.

23.

McKhann

, Knopman

, Chertkow

, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7: 263–269.

24.

Gorelick

, Scuteri

, Black

, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42: 2672–2713.

25.

Bombois

, Debette

, Bruandet

, et al. Vascular subcortical hyperintensities predict conversion to vascular and mixed dementia in MCI patients. Stroke 2008; 39: 2046–2051.

26.

Debette

, Schilling

, Duperron

, et al. Clinical significance of magnetic resonance imaging markers of vascular brain injury: a systematic review and meta-analysis. JAMA Neurol 2019; 76, 81–94.

27.

Staals

, Booth

, Morris

, et al. Total MRI load of cerebral small vessel disease and cognitive ability in older people. Neurobiol Aging 2015; 36: 2806–2811.

28.

Hosoya

, Toi

, Seki

, et al. Association between total cerebral small vessel disease score and cognitive function in patients with vascular risk factors. Hypertens Res 2023; 46: 1326–1334.

29.

Uiterwijk

, van Oostenbrugge

, Huijts

, et al. Total cerebral small vessel disease MRI score is associated with cognitive decline in executive function in patients with hypertension. Front Aging Neurosci 2016; 8: 301.

30.

Zhang

, Tang

, Li

, et al. Total magnetic resonance imaging of cerebral small vessel disease burden predicts dysphagia in patients with a single recent small subcortical infarct. BMC Neurol 2022; 22: 1.

31.

Fandler

, Gattringer

, Eppinger

, et al. Frequency and predictors of dysphagia in patients with recent small subcortical infarcts. Stroke 2017; 48: 213–215.

32.

Loos

, McHutchison

, Cvoro

, et al. The relation between total cerebral small vessel disease burden and gait impairment in patients with minor stroke. Int J Stroke 2018; 13, 518–524.

33.

Hatate

, Miwa

, Matsumoto

, et al. Association between cerebral small vessel diseases and mild parkinsonian signs in the elderly with vascular risk factors. Parkinsonism Relat Disord 2016; 26: 29–34.

34.

, Guo

, Chen

, et al. Influence of pre-existing cerebral small vessel disease on the outcome of acute cardioembolic stroke: a retrospective study. Neuropsychiatr Dis Treat 2022; 18: 899–905.

35.

Taghizadeh

, Martinez-Martin

, Meimandi

, et al. Barthel Index and modified Rankin Scale: Psychometric properties during medication phases in idiopathic Parkinson disease. Ann Phys Rehabil Med 2020; 63: 500–504.

36.

Nakajima

, Miyajima

, Ogino

, et al. Preoperative phosphorylated tau concentration in the cerebrospinal fluid can predict cognitive function three years after shunt surgery in patients with idiopathic normal pressure hydrocephalus. J Alzheimers Dis 2018; 66: 319–331.

37.

Jutten

, Peeters

CFW

, Leijdesdorff

SMJ

, et al. Detecting functional decline from normal aging to dementia: Development and validation of a short version of the Amsterdam IADL Questionnaire. Alzheimers Dement (Amst) 2017; 8: 26–35.