Chronic kidney disease is associated with dementia independent of cerebral small-vessel disease Kaori Miwa, MD Makiko Tanaka, MD Shuhei Okazaki, MD Shigetaka Furukado, MD Yoshiki Yagita, MD Manabu Sakaguchi, MD Hideki Mochizuki, MD Kazuo Kitagawa, MD
Correspondence to Dr. Miwa: [email protected]
ABSTRACT
Objective: To determine whether chronic kidney disease (CKD) is associated with incident dementia independent of cerebral small-vessel disease (SVD) in patients with vascular risk factors.
Methods: Using data from a Japanese cohort of participants with vascular risk factors in an ongoing observational study from 2001, we evaluated the association between CKD at baseline and incident dementia. Baseline brain MRI was used to determine SVD (lacunar infarction, white matter hyperintensities), medial-temporal atrophy, and subcortical atrophy. Cox proportional hazards analyses were performed for predictors of dementia adjusting for age, sex, APOE e4 allele, educational level, baseline Mini-Mental State Examination score, cerebrovascular events, vascular risk factors, and MRI findings. Results: Of the 600 subjects (mean age 68 6 8.3 years, 57% male, 12.8 6 2.6 years of education; CKD: 29%), 50 patients with incident dementia (Alzheimer disease: 24; vascular dementia: 18; mixed-type dementia: 5; other types: 3) were diagnosed during the median 7.5-year follow-up. CKD at baseline was associated with an increased risk of all-cause dementia in models adjusted for age, sex, educational level, and APOE e4 allele. The associations of CKD at baseline remained significant even after additional adjusting for MRI findings and confounding variables (hazard ratio: 1.96 [1.08–3.58], p 5 0.026).
Conclusions: CKD is independently related to the risk of all-cause dementia in patients with vascular risk factors. Our results reinforce the hypothesis that CKD exerts deleterious effects on dementia incidence. Neurology® 2014;82:1051–1057 GLOSSARY AD 5 Alzheimer disease; BCR 5 bicaudate ratio; CDR 5 Clinical Dementia Rating; CKD 5 chronic kidney disease; DSM-III-R 5 Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised; eGFR 5 estimated glomerular filtration rate; LI 5 lacunar infarction; MMSE 5 Mini-Mental State Examination; OSACA2 5 Osaka Follow-up Study for Carotid Atherosclerosis, Part 2; PVH 5 periventricular hyperintensity; SVD 5 small-vessel disease; VaD 5 vascular dementia; WMH 5 white matter hyperintensity.
Supplemental data at Neurology.org
The combination of vascular factors and Alzheimer pathology is common and a potent synergistic cause of cognitive decline at older ages.1 Vascular disease is an important cause of dementia.2 In this context, chronic kidney disease (CKD) has emerged as a possible risk factor for cognitive decline.3 In particular, CKD has been identified as an independent risk factor for future stroke, as well as for subclinical vascular diseases such as cerebral small-vessel diseases (SVD).4 Small-vessel pathology due to endothelial dysfunction has been evoked to explain the connection between kidney and cerebral microvasculature because they share similar anatomical and physiologic characteristics.4 Currently, MRI signs of brain atrophy are widely recognized as established prognostic markers of dementia.5 Furthermore, cerebral SVD is associated with cognitive impairment,6,7 reflecting the estimate of neuropathology or cumulative vascular burden. Several prospective studies relating CKD to cognition have shown conflicting results,8–10 whereas a recent meta-analysis suggested that CKD is a significant risk factor for cognitive impairment.11 The observed differences might partly be explained by differences in study populations, participant diversity, and follow-up time. Furthermore, the potential association between CKD and cognitive impairment has often been explained by the high prevalence of SVD in patients with CKD,12 but it remains unclear whether this association is independent of cerebral SVD. From the Department of Neurology and Stroke Center, Osaka University Graduate School of Medicine, Japan. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2014 American Academy of Neurology
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The aim of this study was to clarify the predictive value of CKD at baseline, while simultaneously controlling for MRI findings, for incident dementia in patients with vascular risk factors who are initially cognitively intact. METHODS The current participants originated from the Osaka Follow-up Study for Carotid Atherosclerosis, Part 2 (OSACA2), an ongoing longitudinal study in which physicians control risk factors in high-risk patients for the primary and secondary prevention of cardiovascular disease.13 Briefly, outpatients who visited the Department of Neurology and Stroke Center at Osaka University Hospital, aged .40 years with more than one vascular risk factor, including hypertension, diabetes, dyslipidemia, history of smoking, established arteriosclerosis documented as TIA, stroke, coronary heart disease, or peripheral artery disease, were enrolled. Patients were excluded from the study if they had experienced a symptomatic vascular event during the previous 3 months. Between January 2001 and December 2009, 729 outpatients who had been enrolled in OSACA2 underwent baseline examinations, including brain MRI and a clinical assessment that included medical history, inquiry into medications, physical and neurologic examinations, blood sampling, and carotid ultrasound. MRI was generally performed to examine lesions in cases with stroke history or suspicious neurologic symptoms (e.g., headache, vertigo, dizziness, numbness, syncope, or subjective memory impairment). The Mini-Mental State Examination (MMSE)14 and the Clinical Dementia Rating (CDR) scale15 were used in all patients to screen suspected cases of cognitive decline. Cognitive tests were administered within 1 month before the MRI examination. Entry inclusion criteria included an MMSE score $24 and 0 on the CDR. Each CDR score was based on interviews with the participant as well as someone familiar with the participant who served as a collateral source. All patients were examined by neurologists. We identified 660 possible participants after
Figure 1
Flowchart of patient recruitment in this study
excluding those who had incomplete baseline examinations (n 5 20) or absent MMSE score (n 5 49). In addition, we excluded patients with suspected previous cognitive impairment (MMSE ,24) (n 5 60). Finally, all analyses were based on 600 patients with complete baseline data (figure 1).
Standard protocol approvals, registrations, and patient consents. This study was approved by the local ethical review board, and all patients provided written informed consent.
MRI protocol and assessment. MRI protocols were described previously.16 The images were analyzed centrally, and all ratings were made by a single experienced observer blinded to the clinical information. Lacunar infarction (LI) was defined as a focal lesion .3 mm and ,15 mm, with a hypointense lesion and hyperintense rim on fluidattenuated inversion recovery images when located supratentorially according to the corresponding hyper- and hypointensity on T2and T1-weighted images, respectively. Silent LI was defined as LI on MRI without any clinical history of cerebrovascular disease. White matter hyperintensities (WMH) were defined as hyperintense signal abnormalities surrounding the ventricles (periventricular hyperintensities [PVH]) and in the deep white matter (deep white matter hyperintensities) on fluid-attenuated inversion recovery images. The degree of WMH was visually rated using the Scheltens Scale with slight modifications: scores of 0 to 6 (0 5 absent, 1 5 ,3 mm in #5, 2 5 ,3 mm in $6, 3 5 4–10 mm in #5, 4 5 4–10 mm in $6, 5 5 ,11 mm in .1, and 6 5 confluent) were given for deep WMH (frontal, temporal, parietal, occipital) (range, 0–24) and scores of 0 to 2 (0 5 absent, 1 5 #5 mm, 2 5 .5 mm, and ,10 mm) were given for PVH (frontal caps, lateral bands, occipital caps) (range, 0–6).17 The sum of ratings was used as a global WMH (range, 0–30). The areas of hyperintensity on T2-weighted images around infarctions and lacunes were not included. We assessed medial temporal lobe atrophy at baseline on T1-weighted images as described previously.18 Briefly, it was evaluated using a 4-point scale (0 5 none, 1 5 questionable, 2 5 apparent, and 3 5 severe) (range, 0–3). In case of asymmetry, the side with more severe atrophy was used for rating. As an estimate of subcortical atrophy, the bicaudate ratio (BCR) was calculated as the minimum intercaudate distance divided by brain width along the same line. Increased BCR is best explained by frontal horn ventricular enlargement due to atrophy of deep frontal subcortical white matter and also associations with global brain atrophy.19 Estimation of kidney function. Baseline kidney function was estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula for Japanese.20 CKD was defined as eGFR ,60 mL/min/1.73 m2. According to the Kidney Disease: Improving Global Outcomes classification,21 we examined eGFR by creating 3 categories: moderate-severe CKD (,45), mild CKD (45–59), and no CKD ($60 mL/min). Potential risk factors. Detailed criteria and references are given in appendix e-1 on the Neurology® Web site at Neurology.org.
MMSE 5 Mini-Mental State Examination; OSACA2 5 Osaka Follow-up Study for Carotid Atherosclerosis, Part 2.13 1052
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Diagnosis of dementia. Cognitive status was assessed prospectively by a neurologist using the MMSE and CDR. Subjects visited outpatient clinic settings to control risk factors (e.g., hypertension and dyslipidemia) every 3 months, 6 months, or 1 year for prevention of stroke.13 Changes in subjects’ general medical conditions were obtained yearly through medical records and interviews. Furthermore, several aspects of everyday cognitively driven functioning to rate participants on the CDR were assessed at every clinical visit. Thus, annual evaluations were performed by trained neurologists and included a medical history, CDR score determination, and standardized neurologic examination. Also, participants were cognitively screened with the MMSE at follow-up visits. The final follow-
up data were collected in June 2011.13 During the follow-up periods, participants with suspected cognitive decline were periodically examined by a neurologist. Clinically significant cognitive impairment was defined as MMSE score ,24 or a decline $1.5 SD of change scores. On the MMSE, this corresponded to a decline $3 points. In addition, subjects were considered to have probable dementia if they had 2 consecutive semiannual CDR scores $1 and did not revert back to normal cognition. Then, subjects suspected to have dementia and cognitive decline (MMSE score ,24, MMSE decline $3, or CDR $1) underwent additional neuropsychological testing.22 To avoid missing incident dementia cases, we also continuously monitored the medical records of all participants at our clinic or other clinics to obtain information on diagnosed dementia and stroke or death. Furthermore, for those patients who could not attend the clinical visit, a phone interview collecting clinical data was performed with the patient and the carer, 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 and etiology, according to the DSM-III-R. Dementia subtypes were diagnosed according to standardized criteria.23,24 Diagnoses were also supported by brain MRI examinations when available. The criteria for mixed dementia were achieved when the investigator considered that the clinical picture presented aspects of both Alzheimer disease (AD) dementia and vascular dementia (VaD).25 Time to dementia was defined as the time between the baseline visit and the date of dementia diagnosis. In addition, subjects were followed until death or refusal of further participation. Those who did not progress to dementia were censored at their last visit.
Statistical analyses. For group comparisons between subjects with and without CKD and between those with and without incident dementia, we used x2 tests for categorical variables and Student t tests for continuous variables. The Kaplan-Meier method with logrank tests was used to compare dementia-free survival for CKD. Analyses were adjusted for variables that have frequently been associated with increased dementia risk. Briefly, the potential confounders were (1) baseline variables associated with the incidence of dementia in univariate analyses, using p , 0.05 as cutoff for significance in this sample, and (2) well-established variables previously found to influence the dementia risk. Therefore, we considered the following independent variables: age, sex, education, APOE e4 allele, baseline MMSE score, hypertension, diabetes, cerebrovascular events (previous and incident as a time-dependent variable), atrophy (medial temporal lobe atrophy, BCR), and SVD (LI or WMH). The hazard ratio from Cox proportional hazards models was used to estimate the risk of dementia associated with CKD (presence or stage) (i.e., CKD, or moderate-severe CKD [,45], mild CKD [45–59], vs no CKD [reference]), adjusted for age, sex, education, and APOE e4 carrier status (model 1). We made an additional adjustment for vascular risk factors (i.e., hypertension, diabetes), cerebrovascular events, and baseline MMSE score (model 2), as well as all MRI findings (atrophy, SVD [presence of LI or WMH]) (model 3). Also, because WMH and LI are strongly associated with each other, we repeated with WMH as SVD, instead of presence of LI in model 3. Because of the lower number of dementia subtypes, we reduced the number of independent variables (age, sex, MMSE score, SVD, and atrophy) due to the known relevance of these factors from previous baseline findings, and controlled the analyses for APOE e4 carrier status and cerebrovascular events (model 4). For the analyses, VaD and mixed dementia were pooled in a single category. Data were analyzed using SAS statistical software (version 9.1; SAS Institute, Cary, NC).
RESULTS The baseline characteristics of study participants are summarized in table 1. A total of 600 patients were included (mean age 68 6 8.3 years, 57% male, 12.8 6 2.6 years of education). Mean eGFR was 68.4 6 17.4 mL/min/1.73 m2, 75% of subjects had hypertension, 29% had CKD, and 44% had LI including 20% who were symptomatic. Compared to subjects with eGFR $60 mL/min/1.73 m2, those with eGFR ,60 (as CKD) were more likely to be older (p , 0.001), male (p 5 0.021), have more hypertension (p 5 0.011), and have higher carotid intima-media thickness (p 5 0.001), PVH (p 5 0.03), and atrophy (p 5 0.002). There were no significant differences in baseline MMSE score (p 5 0.10). From the initial cohort (n 5 600), 84.5% (n 5 507) of the patients could be examined in a clinical visit at the end of follow-up, and 30 patients (5%) had died. Among these 507 patients, 61 patients had a decline in MMSE score of $3 points, and 12 patients had an MMSE score ,24 by the end of follow-up. These 73 patients were subsequently examined using additional neuropsychological testing, and 43 were diagnosed with dementia. Also, using data from telephone interviews or the medical records, we ascertained cognitive status in the remaining 63 patients (10.5% of initial sample), and 7 patients were diagnosed with dementia. Consequently, by the end of the follow-up period (median duration, 7.5 years; range, 2–11 years), all-cause dementia was diagnosed in 50 patients (AD dementia: 24 patients; VaD: 18 patients; mixed-type dementia: 5 patients; other types: 3 patients). Mean interval until the diagnosis of dementia was 5.4 6 2.9 years. Univariate analyses revealed that patients with incident all-cause dementia were significantly older, had CKD, lower baseline MMSE scores, and lower eGFR levels, as well as more SVD and atrophy than patients who did not progress to dementia (table 1). The survival analyses for dementia-free rate curves created with respect to CKD are shown in figure 2. Patients with CKD at baseline were significantly more likely to be diagnosed with dementia (log-rank test: p # 0.0001). Cox multivariate analyses (table 2) showed that the presence of CKD predicted dementia after adjustment for age, sex, education, and APOE e4 carrier status, respectively (model 1). The effects were largely unchanged after additionally entering vascular risk factors, cerebrovascular events, and MMSE score to the analyses (model 2). After further additional adjustment in model 3, which included all MRI findings, CKD remained significant (hazard ratio: 1.96 [1.08–3.58]). When CKD stages were considered, mild CKD was related to an increased risk of allcause dementia despite multivariate adjusting (table 2). However, the difference was borderline associated in moderate-severe CKD (p 5 0.082). Regarding AD dementia in the multivariate analysis (model 4), the presence of CKD and mild CKD Neurology 82
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Table 1
Baseline characteristics in reference to all-cause dementia Dementia All (n 5 600)
Without dementia (n 5 550)
With dementia (n 5 50)
p
Age, y
67.7 6 8.3
67.3 6 8.2
72.1 6 7.4
,0.001
Male
342 (57)
308 (56)
34 (68)
0.11
BMI, kg/m2
23.3 6 2.8
23.2 6 3.0
23.1 6 2.7
0.142
APOE e4 allele
120 (20)
107 (21)
13 (26)
0.341
MMSE score
28.0 6 1.9
28.2 6 1.8
26.2 6 2.1
,0.001
Education, y
12.8 6 2.6
12.8 6 2.3
12.3 6 2.9
0.163
Previous cerebrovascular events
154 (26)
140 (25.6)
14 (28)
0.742
Incident cerebrovascular events
55 (9.2)
47 (8.6)
8 (16)
0.118
Hypertension
450 (75)
412 (75)
38 (76)
0.654
Dyslipidemia
390 (65)
357 (65)
33 (64)
0.884
Diabetes
138 (23)
121 (22)
17 (34)
0.051
Smoking
99 (17)
88 (16)
11 (22)
0.201
68.4 6 17.4
69 6 17
61 6 20
0.003
No CKD
425 (71)
400 (73)
25 (50)
Mild
137 (23)
119 (21)
18 (36)
Moderate-severe
Mean eGFR, mL/min/1.73 m
2
CKD stage
0.001
38 (6)
31 (6)
7 (14)
CKD
175 (29)
150 (27)
25 (50)
Mean IMT, mm
1.12 6 0.40
1.11 6 0.40
1.17 6 0.41
Lacunar infarction
264 (44)
231 (42)
33 (66)
,0.001
Lacunar infarction, n
0 (0–2)
0 (0–2)
2 (0–4)
,0.001
PVH
3 (1–4)
3 (1–4)
4 (2–6)
,0.001
DWMH
5 (2–9)
5 (2–9)
9 (4–15)
,0.001
MTA
1 (1–2)
1 (0–2)
3 (2–3)
,0.001
BCR
0.13 6 0.03
0.13 6 0.03
0.15 6 0.03
,0.001
,0.001 0.424
Abbreviations: BCR 5 bicaudate ratio; BMI 5 body mass index; CKD 5 chronic kidney disease; DWMH 5 deep white matter hyperintensities; eGFR 5 estimated glomerular filtration rate; IMT 5 intima-media thickness; MMSE 5 Mini-Mental State Examination; MTA 5 medial temporal lobe atrophy; PVH 5 periventricular hyperintensities. Data are mean 6 SD, n (%), or median (interquartile range). Brain MRI was performed in all subjects. Participants with eGFR $60 mL/min/1.73 m2 (no CKD group) served as the reference group. No CKD, mild CKD, and moderate-severe CKD were defined as eGFR $60, eGFR 45–60, and eGFR ,45, respectively.
Figure 2
Kaplan-Meier survival analyses of time to dementia diagnosis by baseline chronic kidney disease (CKD)
was associated with an increased risk of AD dementia, respectively. However, regarding VaD, only moderatesevere CKD showed a positive association (table 2). To our knowledge, this is the first study that clearly showed an association between CKD and dementia. Our findings suggest that CKD is an independent risk factor for dementia and that patients with CKD could be medically controlled for prevention of not only cardiovascular events but also dementia. The strengths of our study are the longitudinal study design, use of brain MRI data for determination of SVD and atrophy in all subjects, relatively long follow-up period, the rigorous assessment of diagnosis, and the complete follow-up of all subjects. However, the association between DISCUSSION
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Table 2
Cox proportional hazards regression analyses of baseline CKD markers for all-cause dementia (subtypes) All-cause dementia Model 1
Model 2
Model 3
AD dementia Model 4
VaD Model 4
No CKD, n 5 425 (reference)
1
1
1
1
1
CKD, n 5 175
2.47 (1.30–4.71)
2.08 (1.17–3.69)
1.96 (1.08–3.58)
3.33 (1.41–8.08)
1.41 (0.59–3.31)
p 5 0.006
p 5 0.013
p 5 0.027
p 5 0.004
p 5 0.431
Mild CKD, n 5 137
2.08 (1.13–3.85)
2.01 (1.06–3.73)
1.96 (1.01–3.73)
4.64 (1.79–12.2)
1.01 (0.39–2.59)
p 5 0.021
p 5 0.033
p 5 0.046
p 5 0.002
p 5 0.987
Moderate-severe CKD, n 5 38
2.81 (1.10–6.35)
2.45 (0.94–5.67)
2.29 (0.86–5.39)
1.65 (0.34–5.99)
3.72 (1.01–11.4)
p 5 0.023
p 5 0.065
p 5 0.082
p 5 0.491
p 5 0.049
Abbreviations: AD 5 Alzheimer disease; CKD 5 chronic kidney disease; eGFR 5 estimated glomerular filtration rate; MMSE 5 Mini-Mental State Examination; VaD 5 vascular dementia. Participants with eGFR $60 mL/min/1.73 m2 (no CKD group) served as the reference group. No CKD, mild CKD, and moderate-severe CKD were defined as eGFR $60, eGFR 45–60, and eGFR ,45, respectively. Model 1: adjusted for age, sex, educational level, and APOE e4 carrier status; model 2: adjusted for model 1, vascular risk factors, cerebrovascular events (previous and incident), and baseline MMSE score; model 3: adjusted for model 2 and MRI findings (atrophy and small-vessel disease); and model 4: adjusted for age, sex, APOE e4 carrier status, MMSE score, cerebrovascular events, and MRI findings.
dementia and CKD was seemingly attenuated after adjustment for MRI findings. The potential explanation is that CKD was associated with both vascular risk factors, such as hypertension, and MRI signs of SVD. While the similarity is expected because of shared pathogenesis, it may be related to overlapping features between CKD and SVD. It should be noted that after controlling for vascular risk factors, and/or baseline SVD, the observed effect of incident dementia was relatively weakened, although remained significant for all-cause dementia risk. Furthermore, our results partly support a role for common vascular mechanisms as the underlying pathophysiology of AD dementia. It is possible that CKD and SVD (i.e., diffuse cerebrovascular endothelial failure) are the result of several etiologic pathways developing simultaneously in the context of aging and an accumulated traditional vascular risk factor profile as well as in tandem with the prevalence of nontraditional vascular risk factors caused by renal impairment, such as anemia, oxidative stress, chronic inflammation, and uremic toxins.12 This thereby results in generalized endothelial dysfunction and systemic vascular remodeling.4,26 Few prospective studies have analyzed the relationship of CKD with incident dementia as an outcome.8 Our findings are inconsistent with the recent French population–based 3C study regarding dementia risk. They found no increased risk of cognitive decline or dementia associated with low eGFR levels at baseline. The discrepancy might be explained by the different study populations. The 3C study patients had lower vascular risk backgrounds compared with our Japanese subjects (e.g., racial differences; hypertension: 60% vs 75%; prior stroke: 2.5% vs 30%; CKD: 12% vs 29%; and mean eGFR: 75.8 vs 68.4 mL/min/1.73 m2),
whereas they were similar in several aspects (e.g., age and follow-up time). However, the 3C study also showed that faster eGFR decline during the first 4 years of the follow-up period was related to global cognitive decline and incident dementia to the vascular component.8 This may partly support the hypothesis of a connection between renal impairment and dementia risk. Indeed, a recent meta-analysis including 10 prospective studies showed a significant association of CKD with cognitive impairment.11 Furthermore, numerous structural and functional cerebromicrovascular abnormalities have been identified in AD dementia.27 Endothelial dysfunction, blood-brain barrier disruption, and neurovascular unit dysfunction have been suggested as initial pathogenetic features in both VaD and AD dementia, which could provide a potential link between vascular factors and AD dementia.28 To date, brain atrophy and SVD are common among the elderly population and are considered to be the main determinants of incident dementia.5 Therefore, in this study, we investigated the association between CKD and dementia, considering MRI findings. Our study clearly shows that the relationship is independent of brain atrophy and evidence of SVD, possibly reinforcing not only shared pathophysiology but also an independent contribution by CKD to dementia. This study has several limitations. First, the relatively small number of cases of incident dementia leads to weak statistical power for evaluating dementia subtype. Second, the study may indicate that the use of MRI measures is saturating, i.e., ceiling effects due to visual ratings. Although volumetric measures are preferred over crude visual methods and could lead to different effect sizes, simple visual ratings can be easily applied in clinical settings. Third, albuminuria, another sign of CKD, has also been shown to be a potent independent marker of Neurology 82
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future cardiovascular disease risk and cognitive decline.9,26,29 Unfortunately, we did not investigate albuminuria in all subjects at baseline. Thus, the prognostic value of albuminuria for dementia risk should be confirmed in additional studies. Fourth, our study was limited to a cohort of Japanese individuals with high vascular risk profiles and concomitant SVD burden because MRI was performed for examination of suspected brain disease; thus, our results may not be generalizable to other races and cohorts (e.g., older populations with low cerebrovascular risk profile with CKD). In addition, the relatively high rate of VaD may have occurred because subjects were recruited from our ambulatory setting, which systematically biased recruitment in favor of subjects with a clinical history of stroke or vascular risk. Finally, our baseline measure was the MMSE, a crude measure of cognition that does not capture a slight decline in specific cognitive domains. Nevertheless, the MMSE is a generally and widely used test for the evaluation of cognition. Also, as our outcome measure, clinical diagnosis of dementia was applied to this study using standardized diagnostic criteria in an academic setting. We believe that we detected almost definitive dementia cases. Our longitudinal study found that CKD was independently related to incident dementia in patients with vascular risk factors. CKD per se can be considered as a marker of an individual’s vulnerability to the increased risk of dementia and therefore could be a potential therapeutic target for prevention of dementia. AUTHOR CONTRIBUTIONS Kaori Miwa: study concept and design, data analyses and interpretation, preparation of the manuscript. Makiko Tanaka, Shuhei Okazaki, Shigetaka Furukado, Yoshiki Yagita, and Manabu Sakaguchi: data acquisition. Hideki Mochizuki: study supervision. Kazuo Kitagawa: study concept and design, critical revision of the manuscript for intellectual content, study supervision.
ACKNOWLEDGMENT
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15.
The authors thank C. Kurano and K. Nishiyama for their secretarial assistance.
16. STUDY FUNDING No targeted funding reported.
17. DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
18.
Received August 29, 2013. Accepted in final form December 12, 2013.
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Bombois S, Debette S, Bruandet A, et al. Vascular subcortical hyperintensities predict conversion to vascular and mixed dementia in MCI patients. Stroke 2008;39:2046–2051. Schiffrin EL, Lipman ML, Mann JF. Chronic kidney disease: effects on the cardiovascular system. Circulation 2007;116: 85–97. Yarchoan M, Xie SX, Kling MA, et al. Cerebrovascular atherosclerosis correlates with Alzheimer pathology in neurodegenerative dementias. Brain 2012;135:3749–3756. Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 2008;57:178–201. Kurella Tamura M, Muntner P, Wadley V, et al. Albuminuria, kidney function, and the incidence of cognitive impairment among adults in the United States. Am J Kidney Dis 2011;58:756–763.
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Neurology 82
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Correspondence to Dr. Miwa: [email protected]
ABSTRACT
Objective: To determine whether chronic kidney disease (CKD) is associated with incident dementia independent of cerebral small-vessel disease (SVD) in patients with vascular risk factors.
Methods: Using data from a Japanese cohort of participants with vascular risk factors in an ongoing observational study from 2001, we evaluated the association between CKD at baseline and incident dementia. Baseline brain MRI was used to determine SVD (lacunar infarction, white matter hyperintensities), medial-temporal atrophy, and subcortical atrophy. Cox proportional hazards analyses were performed for predictors of dementia adjusting for age, sex, APOE e4 allele, educational level, baseline Mini-Mental State Examination score, cerebrovascular events, vascular risk factors, and MRI findings. Results: Of the 600 subjects (mean age 68 6 8.3 years, 57% male, 12.8 6 2.6 years of education; CKD: 29%), 50 patients with incident dementia (Alzheimer disease: 24; vascular dementia: 18; mixed-type dementia: 5; other types: 3) were diagnosed during the median 7.5-year follow-up. CKD at baseline was associated with an increased risk of all-cause dementia in models adjusted for age, sex, educational level, and APOE e4 allele. The associations of CKD at baseline remained significant even after additional adjusting for MRI findings and confounding variables (hazard ratio: 1.96 [1.08–3.58], p 5 0.026).
Conclusions: CKD is independently related to the risk of all-cause dementia in patients with vascular risk factors. Our results reinforce the hypothesis that CKD exerts deleterious effects on dementia incidence. Neurology® 2014;82:1051–1057 GLOSSARY AD 5 Alzheimer disease; BCR 5 bicaudate ratio; CDR 5 Clinical Dementia Rating; CKD 5 chronic kidney disease; DSM-III-R 5 Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised; eGFR 5 estimated glomerular filtration rate; LI 5 lacunar infarction; MMSE 5 Mini-Mental State Examination; OSACA2 5 Osaka Follow-up Study for Carotid Atherosclerosis, Part 2; PVH 5 periventricular hyperintensity; SVD 5 small-vessel disease; VaD 5 vascular dementia; WMH 5 white matter hyperintensity.
Supplemental data at Neurology.org
The combination of vascular factors and Alzheimer pathology is common and a potent synergistic cause of cognitive decline at older ages.1 Vascular disease is an important cause of dementia.2 In this context, chronic kidney disease (CKD) has emerged as a possible risk factor for cognitive decline.3 In particular, CKD has been identified as an independent risk factor for future stroke, as well as for subclinical vascular diseases such as cerebral small-vessel diseases (SVD).4 Small-vessel pathology due to endothelial dysfunction has been evoked to explain the connection between kidney and cerebral microvasculature because they share similar anatomical and physiologic characteristics.4 Currently, MRI signs of brain atrophy are widely recognized as established prognostic markers of dementia.5 Furthermore, cerebral SVD is associated with cognitive impairment,6,7 reflecting the estimate of neuropathology or cumulative vascular burden. Several prospective studies relating CKD to cognition have shown conflicting results,8–10 whereas a recent meta-analysis suggested that CKD is a significant risk factor for cognitive impairment.11 The observed differences might partly be explained by differences in study populations, participant diversity, and follow-up time. Furthermore, the potential association between CKD and cognitive impairment has often been explained by the high prevalence of SVD in patients with CKD,12 but it remains unclear whether this association is independent of cerebral SVD. From the Department of Neurology and Stroke Center, Osaka University Graduate School of Medicine, Japan. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2014 American Academy of Neurology
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The aim of this study was to clarify the predictive value of CKD at baseline, while simultaneously controlling for MRI findings, for incident dementia in patients with vascular risk factors who are initially cognitively intact. METHODS The current participants originated from the Osaka Follow-up Study for Carotid Atherosclerosis, Part 2 (OSACA2), an ongoing longitudinal study in which physicians control risk factors in high-risk patients for the primary and secondary prevention of cardiovascular disease.13 Briefly, outpatients who visited the Department of Neurology and Stroke Center at Osaka University Hospital, aged .40 years with more than one vascular risk factor, including hypertension, diabetes, dyslipidemia, history of smoking, established arteriosclerosis documented as TIA, stroke, coronary heart disease, or peripheral artery disease, were enrolled. Patients were excluded from the study if they had experienced a symptomatic vascular event during the previous 3 months. Between January 2001 and December 2009, 729 outpatients who had been enrolled in OSACA2 underwent baseline examinations, including brain MRI and a clinical assessment that included medical history, inquiry into medications, physical and neurologic examinations, blood sampling, and carotid ultrasound. MRI was generally performed to examine lesions in cases with stroke history or suspicious neurologic symptoms (e.g., headache, vertigo, dizziness, numbness, syncope, or subjective memory impairment). The Mini-Mental State Examination (MMSE)14 and the Clinical Dementia Rating (CDR) scale15 were used in all patients to screen suspected cases of cognitive decline. Cognitive tests were administered within 1 month before the MRI examination. Entry inclusion criteria included an MMSE score $24 and 0 on the CDR. Each CDR score was based on interviews with the participant as well as someone familiar with the participant who served as a collateral source. All patients were examined by neurologists. We identified 660 possible participants after
Figure 1
Flowchart of patient recruitment in this study
excluding those who had incomplete baseline examinations (n 5 20) or absent MMSE score (n 5 49). In addition, we excluded patients with suspected previous cognitive impairment (MMSE ,24) (n 5 60). Finally, all analyses were based on 600 patients with complete baseline data (figure 1).
Standard protocol approvals, registrations, and patient consents. This study was approved by the local ethical review board, and all patients provided written informed consent.
MRI protocol and assessment. MRI protocols were described previously.16 The images were analyzed centrally, and all ratings were made by a single experienced observer blinded to the clinical information. Lacunar infarction (LI) was defined as a focal lesion .3 mm and ,15 mm, with a hypointense lesion and hyperintense rim on fluidattenuated inversion recovery images when located supratentorially according to the corresponding hyper- and hypointensity on T2and T1-weighted images, respectively. Silent LI was defined as LI on MRI without any clinical history of cerebrovascular disease. White matter hyperintensities (WMH) were defined as hyperintense signal abnormalities surrounding the ventricles (periventricular hyperintensities [PVH]) and in the deep white matter (deep white matter hyperintensities) on fluid-attenuated inversion recovery images. The degree of WMH was visually rated using the Scheltens Scale with slight modifications: scores of 0 to 6 (0 5 absent, 1 5 ,3 mm in #5, 2 5 ,3 mm in $6, 3 5 4–10 mm in #5, 4 5 4–10 mm in $6, 5 5 ,11 mm in .1, and 6 5 confluent) were given for deep WMH (frontal, temporal, parietal, occipital) (range, 0–24) and scores of 0 to 2 (0 5 absent, 1 5 #5 mm, 2 5 .5 mm, and ,10 mm) were given for PVH (frontal caps, lateral bands, occipital caps) (range, 0–6).17 The sum of ratings was used as a global WMH (range, 0–30). The areas of hyperintensity on T2-weighted images around infarctions and lacunes were not included. We assessed medial temporal lobe atrophy at baseline on T1-weighted images as described previously.18 Briefly, it was evaluated using a 4-point scale (0 5 none, 1 5 questionable, 2 5 apparent, and 3 5 severe) (range, 0–3). In case of asymmetry, the side with more severe atrophy was used for rating. As an estimate of subcortical atrophy, the bicaudate ratio (BCR) was calculated as the minimum intercaudate distance divided by brain width along the same line. Increased BCR is best explained by frontal horn ventricular enlargement due to atrophy of deep frontal subcortical white matter and also associations with global brain atrophy.19 Estimation of kidney function. Baseline kidney function was estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula for Japanese.20 CKD was defined as eGFR ,60 mL/min/1.73 m2. According to the Kidney Disease: Improving Global Outcomes classification,21 we examined eGFR by creating 3 categories: moderate-severe CKD (,45), mild CKD (45–59), and no CKD ($60 mL/min). Potential risk factors. Detailed criteria and references are given in appendix e-1 on the Neurology® Web site at Neurology.org.
MMSE 5 Mini-Mental State Examination; OSACA2 5 Osaka Follow-up Study for Carotid Atherosclerosis, Part 2.13 1052
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Diagnosis of dementia. Cognitive status was assessed prospectively by a neurologist using the MMSE and CDR. Subjects visited outpatient clinic settings to control risk factors (e.g., hypertension and dyslipidemia) every 3 months, 6 months, or 1 year for prevention of stroke.13 Changes in subjects’ general medical conditions were obtained yearly through medical records and interviews. Furthermore, several aspects of everyday cognitively driven functioning to rate participants on the CDR were assessed at every clinical visit. Thus, annual evaluations were performed by trained neurologists and included a medical history, CDR score determination, and standardized neurologic examination. Also, participants were cognitively screened with the MMSE at follow-up visits. The final follow-
up data were collected in June 2011.13 During the follow-up periods, participants with suspected cognitive decline were periodically examined by a neurologist. Clinically significant cognitive impairment was defined as MMSE score ,24 or a decline $1.5 SD of change scores. On the MMSE, this corresponded to a decline $3 points. In addition, subjects were considered to have probable dementia if they had 2 consecutive semiannual CDR scores $1 and did not revert back to normal cognition. Then, subjects suspected to have dementia and cognitive decline (MMSE score ,24, MMSE decline $3, or CDR $1) underwent additional neuropsychological testing.22 To avoid missing incident dementia cases, we also continuously monitored the medical records of all participants at our clinic or other clinics to obtain information on diagnosed dementia and stroke or death. Furthermore, for those patients who could not attend the clinical visit, a phone interview collecting clinical data was performed with the patient and the carer, 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 and etiology, according to the DSM-III-R. Dementia subtypes were diagnosed according to standardized criteria.23,24 Diagnoses were also supported by brain MRI examinations when available. The criteria for mixed dementia were achieved when the investigator considered that the clinical picture presented aspects of both Alzheimer disease (AD) dementia and vascular dementia (VaD).25 Time to dementia was defined as the time between the baseline visit and the date of dementia diagnosis. In addition, subjects were followed until death or refusal of further participation. Those who did not progress to dementia were censored at their last visit.
Statistical analyses. For group comparisons between subjects with and without CKD and between those with and without incident dementia, we used x2 tests for categorical variables and Student t tests for continuous variables. The Kaplan-Meier method with logrank tests was used to compare dementia-free survival for CKD. Analyses were adjusted for variables that have frequently been associated with increased dementia risk. Briefly, the potential confounders were (1) baseline variables associated with the incidence of dementia in univariate analyses, using p , 0.05 as cutoff for significance in this sample, and (2) well-established variables previously found to influence the dementia risk. Therefore, we considered the following independent variables: age, sex, education, APOE e4 allele, baseline MMSE score, hypertension, diabetes, cerebrovascular events (previous and incident as a time-dependent variable), atrophy (medial temporal lobe atrophy, BCR), and SVD (LI or WMH). The hazard ratio from Cox proportional hazards models was used to estimate the risk of dementia associated with CKD (presence or stage) (i.e., CKD, or moderate-severe CKD [,45], mild CKD [45–59], vs no CKD [reference]), adjusted for age, sex, education, and APOE e4 carrier status (model 1). We made an additional adjustment for vascular risk factors (i.e., hypertension, diabetes), cerebrovascular events, and baseline MMSE score (model 2), as well as all MRI findings (atrophy, SVD [presence of LI or WMH]) (model 3). Also, because WMH and LI are strongly associated with each other, we repeated with WMH as SVD, instead of presence of LI in model 3. Because of the lower number of dementia subtypes, we reduced the number of independent variables (age, sex, MMSE score, SVD, and atrophy) due to the known relevance of these factors from previous baseline findings, and controlled the analyses for APOE e4 carrier status and cerebrovascular events (model 4). For the analyses, VaD and mixed dementia were pooled in a single category. Data were analyzed using SAS statistical software (version 9.1; SAS Institute, Cary, NC).
RESULTS The baseline characteristics of study participants are summarized in table 1. A total of 600 patients were included (mean age 68 6 8.3 years, 57% male, 12.8 6 2.6 years of education). Mean eGFR was 68.4 6 17.4 mL/min/1.73 m2, 75% of subjects had hypertension, 29% had CKD, and 44% had LI including 20% who were symptomatic. Compared to subjects with eGFR $60 mL/min/1.73 m2, those with eGFR ,60 (as CKD) were more likely to be older (p , 0.001), male (p 5 0.021), have more hypertension (p 5 0.011), and have higher carotid intima-media thickness (p 5 0.001), PVH (p 5 0.03), and atrophy (p 5 0.002). There were no significant differences in baseline MMSE score (p 5 0.10). From the initial cohort (n 5 600), 84.5% (n 5 507) of the patients could be examined in a clinical visit at the end of follow-up, and 30 patients (5%) had died. Among these 507 patients, 61 patients had a decline in MMSE score of $3 points, and 12 patients had an MMSE score ,24 by the end of follow-up. These 73 patients were subsequently examined using additional neuropsychological testing, and 43 were diagnosed with dementia. Also, using data from telephone interviews or the medical records, we ascertained cognitive status in the remaining 63 patients (10.5% of initial sample), and 7 patients were diagnosed with dementia. Consequently, by the end of the follow-up period (median duration, 7.5 years; range, 2–11 years), all-cause dementia was diagnosed in 50 patients (AD dementia: 24 patients; VaD: 18 patients; mixed-type dementia: 5 patients; other types: 3 patients). Mean interval until the diagnosis of dementia was 5.4 6 2.9 years. Univariate analyses revealed that patients with incident all-cause dementia were significantly older, had CKD, lower baseline MMSE scores, and lower eGFR levels, as well as more SVD and atrophy than patients who did not progress to dementia (table 1). The survival analyses for dementia-free rate curves created with respect to CKD are shown in figure 2. Patients with CKD at baseline were significantly more likely to be diagnosed with dementia (log-rank test: p # 0.0001). Cox multivariate analyses (table 2) showed that the presence of CKD predicted dementia after adjustment for age, sex, education, and APOE e4 carrier status, respectively (model 1). The effects were largely unchanged after additionally entering vascular risk factors, cerebrovascular events, and MMSE score to the analyses (model 2). After further additional adjustment in model 3, which included all MRI findings, CKD remained significant (hazard ratio: 1.96 [1.08–3.58]). When CKD stages were considered, mild CKD was related to an increased risk of allcause dementia despite multivariate adjusting (table 2). However, the difference was borderline associated in moderate-severe CKD (p 5 0.082). Regarding AD dementia in the multivariate analysis (model 4), the presence of CKD and mild CKD Neurology 82
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Table 1
Baseline characteristics in reference to all-cause dementia Dementia All (n 5 600)
Without dementia (n 5 550)
With dementia (n 5 50)
p
Age, y
67.7 6 8.3
67.3 6 8.2
72.1 6 7.4
,0.001
Male
342 (57)
308 (56)
34 (68)
0.11
BMI, kg/m2
23.3 6 2.8
23.2 6 3.0
23.1 6 2.7
0.142
APOE e4 allele
120 (20)
107 (21)
13 (26)
0.341
MMSE score
28.0 6 1.9
28.2 6 1.8
26.2 6 2.1
,0.001
Education, y
12.8 6 2.6
12.8 6 2.3
12.3 6 2.9
0.163
Previous cerebrovascular events
154 (26)
140 (25.6)
14 (28)
0.742
Incident cerebrovascular events
55 (9.2)
47 (8.6)
8 (16)
0.118
Hypertension
450 (75)
412 (75)
38 (76)
0.654
Dyslipidemia
390 (65)
357 (65)
33 (64)
0.884
Diabetes
138 (23)
121 (22)
17 (34)
0.051
Smoking
99 (17)
88 (16)
11 (22)
0.201
68.4 6 17.4
69 6 17
61 6 20
0.003
No CKD
425 (71)
400 (73)
25 (50)
Mild
137 (23)
119 (21)
18 (36)
Moderate-severe
Mean eGFR, mL/min/1.73 m
2
CKD stage
0.001
38 (6)
31 (6)
7 (14)
CKD
175 (29)
150 (27)
25 (50)
Mean IMT, mm
1.12 6 0.40
1.11 6 0.40
1.17 6 0.41
Lacunar infarction
264 (44)
231 (42)
33 (66)
,0.001
Lacunar infarction, n
0 (0–2)
0 (0–2)
2 (0–4)
,0.001
PVH
3 (1–4)
3 (1–4)
4 (2–6)
,0.001
DWMH
5 (2–9)
5 (2–9)
9 (4–15)
,0.001
MTA
1 (1–2)
1 (0–2)
3 (2–3)
,0.001
BCR
0.13 6 0.03
0.13 6 0.03
0.15 6 0.03
,0.001
,0.001 0.424
Abbreviations: BCR 5 bicaudate ratio; BMI 5 body mass index; CKD 5 chronic kidney disease; DWMH 5 deep white matter hyperintensities; eGFR 5 estimated glomerular filtration rate; IMT 5 intima-media thickness; MMSE 5 Mini-Mental State Examination; MTA 5 medial temporal lobe atrophy; PVH 5 periventricular hyperintensities. Data are mean 6 SD, n (%), or median (interquartile range). Brain MRI was performed in all subjects. Participants with eGFR $60 mL/min/1.73 m2 (no CKD group) served as the reference group. No CKD, mild CKD, and moderate-severe CKD were defined as eGFR $60, eGFR 45–60, and eGFR ,45, respectively.
Figure 2
Kaplan-Meier survival analyses of time to dementia diagnosis by baseline chronic kidney disease (CKD)
was associated with an increased risk of AD dementia, respectively. However, regarding VaD, only moderatesevere CKD showed a positive association (table 2). To our knowledge, this is the first study that clearly showed an association between CKD and dementia. Our findings suggest that CKD is an independent risk factor for dementia and that patients with CKD could be medically controlled for prevention of not only cardiovascular events but also dementia. The strengths of our study are the longitudinal study design, use of brain MRI data for determination of SVD and atrophy in all subjects, relatively long follow-up period, the rigorous assessment of diagnosis, and the complete follow-up of all subjects. However, the association between DISCUSSION
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Table 2
Cox proportional hazards regression analyses of baseline CKD markers for all-cause dementia (subtypes) All-cause dementia Model 1
Model 2
Model 3
AD dementia Model 4
VaD Model 4
No CKD, n 5 425 (reference)
1
1
1
1
1
CKD, n 5 175
2.47 (1.30–4.71)
2.08 (1.17–3.69)
1.96 (1.08–3.58)
3.33 (1.41–8.08)
1.41 (0.59–3.31)
p 5 0.006
p 5 0.013
p 5 0.027
p 5 0.004
p 5 0.431
Mild CKD, n 5 137
2.08 (1.13–3.85)
2.01 (1.06–3.73)
1.96 (1.01–3.73)
4.64 (1.79–12.2)
1.01 (0.39–2.59)
p 5 0.021
p 5 0.033
p 5 0.046
p 5 0.002
p 5 0.987
Moderate-severe CKD, n 5 38
2.81 (1.10–6.35)
2.45 (0.94–5.67)
2.29 (0.86–5.39)
1.65 (0.34–5.99)
3.72 (1.01–11.4)
p 5 0.023
p 5 0.065
p 5 0.082
p 5 0.491
p 5 0.049
Abbreviations: AD 5 Alzheimer disease; CKD 5 chronic kidney disease; eGFR 5 estimated glomerular filtration rate; MMSE 5 Mini-Mental State Examination; VaD 5 vascular dementia. Participants with eGFR $60 mL/min/1.73 m2 (no CKD group) served as the reference group. No CKD, mild CKD, and moderate-severe CKD were defined as eGFR $60, eGFR 45–60, and eGFR ,45, respectively. Model 1: adjusted for age, sex, educational level, and APOE e4 carrier status; model 2: adjusted for model 1, vascular risk factors, cerebrovascular events (previous and incident), and baseline MMSE score; model 3: adjusted for model 2 and MRI findings (atrophy and small-vessel disease); and model 4: adjusted for age, sex, APOE e4 carrier status, MMSE score, cerebrovascular events, and MRI findings.
dementia and CKD was seemingly attenuated after adjustment for MRI findings. The potential explanation is that CKD was associated with both vascular risk factors, such as hypertension, and MRI signs of SVD. While the similarity is expected because of shared pathogenesis, it may be related to overlapping features between CKD and SVD. It should be noted that after controlling for vascular risk factors, and/or baseline SVD, the observed effect of incident dementia was relatively weakened, although remained significant for all-cause dementia risk. Furthermore, our results partly support a role for common vascular mechanisms as the underlying pathophysiology of AD dementia. It is possible that CKD and SVD (i.e., diffuse cerebrovascular endothelial failure) are the result of several etiologic pathways developing simultaneously in the context of aging and an accumulated traditional vascular risk factor profile as well as in tandem with the prevalence of nontraditional vascular risk factors caused by renal impairment, such as anemia, oxidative stress, chronic inflammation, and uremic toxins.12 This thereby results in generalized endothelial dysfunction and systemic vascular remodeling.4,26 Few prospective studies have analyzed the relationship of CKD with incident dementia as an outcome.8 Our findings are inconsistent with the recent French population–based 3C study regarding dementia risk. They found no increased risk of cognitive decline or dementia associated with low eGFR levels at baseline. The discrepancy might be explained by the different study populations. The 3C study patients had lower vascular risk backgrounds compared with our Japanese subjects (e.g., racial differences; hypertension: 60% vs 75%; prior stroke: 2.5% vs 30%; CKD: 12% vs 29%; and mean eGFR: 75.8 vs 68.4 mL/min/1.73 m2),
whereas they were similar in several aspects (e.g., age and follow-up time). However, the 3C study also showed that faster eGFR decline during the first 4 years of the follow-up period was related to global cognitive decline and incident dementia to the vascular component.8 This may partly support the hypothesis of a connection between renal impairment and dementia risk. Indeed, a recent meta-analysis including 10 prospective studies showed a significant association of CKD with cognitive impairment.11 Furthermore, numerous structural and functional cerebromicrovascular abnormalities have been identified in AD dementia.27 Endothelial dysfunction, blood-brain barrier disruption, and neurovascular unit dysfunction have been suggested as initial pathogenetic features in both VaD and AD dementia, which could provide a potential link between vascular factors and AD dementia.28 To date, brain atrophy and SVD are common among the elderly population and are considered to be the main determinants of incident dementia.5 Therefore, in this study, we investigated the association between CKD and dementia, considering MRI findings. Our study clearly shows that the relationship is independent of brain atrophy and evidence of SVD, possibly reinforcing not only shared pathophysiology but also an independent contribution by CKD to dementia. This study has several limitations. First, the relatively small number of cases of incident dementia leads to weak statistical power for evaluating dementia subtype. Second, the study may indicate that the use of MRI measures is saturating, i.e., ceiling effects due to visual ratings. Although volumetric measures are preferred over crude visual methods and could lead to different effect sizes, simple visual ratings can be easily applied in clinical settings. Third, albuminuria, another sign of CKD, has also been shown to be a potent independent marker of Neurology 82
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future cardiovascular disease risk and cognitive decline.9,26,29 Unfortunately, we did not investigate albuminuria in all subjects at baseline. Thus, the prognostic value of albuminuria for dementia risk should be confirmed in additional studies. Fourth, our study was limited to a cohort of Japanese individuals with high vascular risk profiles and concomitant SVD burden because MRI was performed for examination of suspected brain disease; thus, our results may not be generalizable to other races and cohorts (e.g., older populations with low cerebrovascular risk profile with CKD). In addition, the relatively high rate of VaD may have occurred because subjects were recruited from our ambulatory setting, which systematically biased recruitment in favor of subjects with a clinical history of stroke or vascular risk. Finally, our baseline measure was the MMSE, a crude measure of cognition that does not capture a slight decline in specific cognitive domains. Nevertheless, the MMSE is a generally and widely used test for the evaluation of cognition. Also, as our outcome measure, clinical diagnosis of dementia was applied to this study using standardized diagnostic criteria in an academic setting. We believe that we detected almost definitive dementia cases. Our longitudinal study found that CKD was independently related to incident dementia in patients with vascular risk factors. CKD per se can be considered as a marker of an individual’s vulnerability to the increased risk of dementia and therefore could be a potential therapeutic target for prevention of dementia. AUTHOR CONTRIBUTIONS Kaori Miwa: study concept and design, data analyses and interpretation, preparation of the manuscript. Makiko Tanaka, Shuhei Okazaki, Shigetaka Furukado, Yoshiki Yagita, and Manabu Sakaguchi: data acquisition. Hideki Mochizuki: study supervision. Kazuo Kitagawa: study concept and design, critical revision of the manuscript for intellectual content, study supervision.
ACKNOWLEDGMENT
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
The authors thank C. Kurano and K. Nishiyama for their secretarial assistance.
16. STUDY FUNDING No targeted funding reported.
17. DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
18.
Received August 29, 2013. Accepted in final form December 12, 2013.
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Neurology 82
March 25, 2014
1057
