Neurobiology of Aging xxx (2014) 1e8
Contents lists available at ScienceDirect
Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging
Hippocampal perivascular spaces are related to aging and blood pressure but not to cognition Ming Yao a, b, Yi-cheng Zhu a, Aïcha Soumaré c, d, Carole Dufouil c, d, Bernard Mazoyer e, f, g, h, i, Christophe Tzourio c, d, Hugues Chabriat b, j, k, * a
Department of Neurology, Peking Union Medical College Hospital, Beijing, China Univ Paris Diderot, Sorbonne Paris Cité, Paris, France Univ Pierre et Marie Curie Paris 6, Paris, France d INSERM UMR708, Bordeaux, France e Institut Universitaire de France, Paris, France f CNRS-CEA UMR 6232, Caen, France g Groupe Imagerie Neurofonctionelle, Caen, France h University Caen Basse-Normandie, Caen, France i CHU de Caen, Caen, France j INSERM UMR 1161 and DHU NeuroVasc, Paris, France k Department of Neurology, AP-HP, Paris, France b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 October 2013 Received in revised form 11 March 2014 Accepted 14 March 2014
The risk factors of hippocampal dilated perivascular spaces (H-dPVS), their radiological relevance and their impact on cognitive performance remain under investigation. These aspects were evaluated in 1818 stroke- and dementia-free participants enrolled in the 3C-Dijon MRI study, using logistic regression, multiple linear regression, and Cox models. At study entry, the load of H-dPVS was found strongly associated with age and hypertension (degree 2 vs. degree 0: odds ratio: 1.16; 95% confidence interval: 1.02e1.33 and odds ratio: 1.98; 95% confidence interval: 1.39e2.81, respectively) and positively related to the presence of lacunar infarcts, white-matter hyperintensities volume, and hippocampal volume (p 0.024). Load of H-dPVS was not related to baseline cognitive performance (p > 0.05). Cox regression modeling did not show a significant relationship between the load of H-dPVS and incident dementia risk (p > 0.05). The present results support that both aging and blood pressure do play a key role in the development of H-dPVS in the older population. In contrast with the dilated perivascular spaces located in white matter or basal ganglia, the load of H-dPVS does not appear associated with occurrence of dementia. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Hippocampal dilated perivascular spaces Risk factors MRI Cognition
1. Introduction Dilated perivascular spaces (dPVS) are commonly described from magnetic resonance imaging (MRI) in basal ganglia and in different subcortical white-matter regions (Chen et al., 2011; Cumurciuc et al., 2006; Groeschel et al., 2006; Maclullich et al., 2004; Patankar et al., 2005; Rouhl et al., 2008; Zhu et al., 2010a), while only a few studies have focused on hippocampal dilated perivascular spaces (H-dPVS) (Barboriak et al., 2000; Bartrés-Faz et al., 2001; Bastos-Leite et al., 2006; Chen et al., 2011; Li et al., 2006; Maclullich et al., 2004; Nakada et al., 2005; Sasaki et al., 1993; Yoneoka et al., 2002). The exact relationships between pathologic * Corresponding author at: Service de Neurologie, Hôpital Lariboisière, 2 rue Ambroise Paré, 75010 Paris, France. Tel.: þ33 1 49 95 25 93; fax: þ33 1 49 95 25 96. E-mail address: [email protected] (H. Chabriat). 0197-4580/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2014.03.021
data and the radiological aspects of H-dPVS as well as their exact clinical correlates are still debated. Various radiological terminologies, such as “cavities” or “sulcal cavities”, have been previously used for these lesions (Barboriak et al., 2000; Bartrés-Faz et al., 2001; Bastos-Leite et al., 2006; Li et al., 2006; Nakada et al., 2005; Sasaki et al., 1993; Yoneoka et al., 2002). However, histologic analyses strongly support that these “cavities” actually correspond to dilated cystic tissue remnants containing small perforating vessels and resulting from incomplete fusion of the hippocampus fissure during development (Sasaki et al., 1993). In the literature, the prevalence of H-dPVS seems to vary largely in healthy older populations (from 36.4% to 77%) (Barboriak et al., 2000; Li et al., 2006; Maclullich et al., 2004; Yoneoka et al., 2002). In most studies, a higher prevalence of H-dPVS is observed with aging (Barboriak et al., 2000; Sasaki et al., 1993; Yoneoka et al., 2002) although this was not confirmed by all authors (Chen et al., 2011; Li et al., 2006).
2
M. Yao et al. / Neurobiology of Aging xxx (2014) 1e8
In older individuals, the severity of dPVS in basal ganglia or white matter was recently found associated with an increased risk of cognitive decline or incident dementia (Maclullich et al., 2004; Zhu et al., 2010b). Since hippocampus plays a key role in memory performance (Frisoni et al., 2008; Lazarov et al., 2010; Sahay et al., 2011; Squire, 1992), the development of H-dPVS may be also related to cognitive performance in older people. However, their impact on cognition has been previously evaluated only in limited-samples and remains controversial. H-dPVS have been associated respectively with transient global amnesia or cognitive decline (Chen et al., 2011; Nakada et al., 2005). Conversely, other reports suggested that a higher number of hippocampal cerebrospinal fluid (CSF) spaces was not related to global cognitive performance (Bartrés-Faz et al., 2001; Maclullich et al., 2004) and was even possibly related to a lower risk of Alzheimer’s disease in a study of limited sample-size (Li et al., 2006). Otherwise, H-dPVS have not been found related to white-matter hyperintensities (WMH) (Barboriak et al., 2000; Chen et al., 2011), though the severity of dPVS in other cerebral areas has repeatedly shown to be a marker of cerebral small vessel disease (SVD) strongly related to the accumulation of lacunar infarcts, white-matter hyperintensities or microbleeds (Doubal et al., 2010; Patankar et al., 2005; Rouhl et al., 2008). In this study based on data collected in a large-sample of community-dwelling older individuals, we aimed at (1) investigating the risk factors of H-dPVS and their relationships with the other classical MRI markers of SVD; and (2) determining their impact on baseline cognitive performance or incident dementia over 8-years of follow-up. 2. Methods 2.1. Participants Data were obtained from the 3C-Dijon MRI study, a cohort study of community-dwelling persons aged 65 years and older, randomly selected from the electoral rolls in the city of Dijon France. The complete study protocol, approved by the Ethical Committee of the University-Hospital of Bicêtre, has been detailed elsewhere (3C Study Group, 2003). All participants gave a signed informed consent. Among the 4931 participants included in Dijon, those 0.05). In preliminary analyses, we observed that age, APOE genotype, and depressive symptoms were the strongest predictors of dementia among the potential studied risk factors, while education level, age, depressive symptoms, gender, and number of cardiovascular diseases or risk factors were associated with cognition (at least 1 cognitive test) (data not shown). Multiple linear regression models (dependent variables ¼ each baseline cognitive score) and Cox proportional hazard models were performed to evaluate the relationships between the severity of H-dPVS and different baseline cognitive performance or incident dementia. Because cognitive tests scores were not normally distributed, they were logtransformed. Analyses for association between the severity of HdPVS and cognition or dementia were performed in 3 steps. First, age, gender, and education level were controlled (model 1). A preliminary search for potential interaction between H-dPVS and age, gender, or education level in relation to the different outcomes (cognitive function and dementia) was performed, but none was significant. Second, models were further adjusted for covariates that were associated with dementia, cognition (at least 1 cognitive test) or for covariates known to be risk factors for dementia or cognitive function, that is, APOE genotype, depressive symptoms, and number of cardiovascular diseases or risk factors (model 2). Third, to assess whether other brain lesions or cerebral atrophy could modify the association between H-dPVS and cognitive performance or incident dementia, additional adjustments for WMH volume, the presence and/or the absence of brain infarcts, and brain parenchymal fraction were obtained (model 3). Statistical analyses were performed using SPSS version 20.0 for Windows (SPSS Inc). All p-values were 2-tailed and criteria for significance were p < 0.05. 3. Results 3.1. Baseline characteristics The demographic, clinical, and main MRI features at baseline are summarized in Table 1. The mean age of participants was 72.46 years (SD ¼ 4.14), 38.8% (n ¼ 706) participants were men. Regarding H-dPVS, 44.5% of individuals had at least 1 H-dPVS with a maximum number of 10. 3.2. Risk factors of H-dPVS As shown in Table 2, the load of H-dPVS increased with age; each SD increase in age was associated with a higher odds of H-dPVS (for degree 2 vs. degree 0: odds ratio [OR] 1.16; 95% confidence interval [CI]: 1.02e1.33, p ¼ 0.022). Comparison of degree 1 and degree 0 resulted in a similar but nonsignificant trend (p ¼ 0.08). After adjustment for age and gender, the load of H-dPVS was found to increase both with systolic and with diastolic blood pressure (p 0.037). Baseline hypertension was also associated with H-dPVS with a doubling of the adjusted odds when degree 2 was compared with degree 0 (p < 0.001). No interaction was detected between age and blood pressure on the load of H-dPVS. HdPVS of degree 2 was also significantly related to the use of antihypertensive drugs (p < 0.001). In contrast, the load of H-dPVS was not found related to gender, smoking or drinking status,
Table 1 Main characteristics of the cohort (N ¼ 1818) Characteristics Age (y), mean SD (range) Male gender Hypertension Hypercholesterolemia Diabetes Ischemic heart disease Current smoker Current drinker Apolipoprotein E4 allele carrier Cognitive scores Mini-Mental State Examination score, mean SD BENTON visual, mean SD Isaacs set test, mean SD Trail making tests part A, mean SD Trail making tests part B, mean SD MRI markers Absolute volume of WMH in cm3, mean SD Presence of lacunar infarcts Absolute volume of gray matter in cm3, mean SD Absolute volume of hippocampus in cm3, mean SD BPF, mean SD Number of H-dPVS 0 1e2 >2
72.46 4.14 (65e85) 38.8% (706) 76.8% (1396) 56.8% (1025) 8.3% (150) 8.1% (147) 5.9% (108) 80.0% (1450) 22.0% (396) 27.67 1.87 11.73 1.91 34.07 6.73 2.22 0.83 6.69 8.44 5.54 5.04 6.8% (121) 508.18 51.03 6.61 0.85 71.82 3.2 55.5% (1009) 28.5% (519) 16.0% (290)
Key: BPF, brain parenchymal fraction; H-dPVS, dilated perivascular spaces in hippocampus; MRI, magnetic resonance imaging; SD, standard deviation; WMH, whitematter hyperintensities.
hypercholesterolemia, diabetes, ischemic heart disease, or APOE4 genotype. 3.3. Relationships between the severity of H-dPVS and the other MRI markers of SVD As shown in Table 3, participants with H-dPVS of degree 2 had the highest prevalence of lacunar infarcts and the highest volume of WMH, deep WMH, and perivascular WMH, whereas the contrary was found for those with degree 0. After adjustment for age, gender, and total intracranial volume, degree 2 of H-dPVS (vs. degree 0) was found strongly related to the total WMH volume (p < 0.001,OR: 1.34; 95% CI: 1.19e1.51). Degree 2 of H-dPVS was also found significantly related both to the volume of deep WMH and to that of perivascular WMH (p < 0.001), and associated with the presence of lacunar infarcts (p ¼ 0.007). Conversely, no significant association was detected for degree 1 neither with the WMH volume (p ¼ 0.11) nor with the presence of lacunar infarcts (p ¼ 0.12) although a similar trend was detected. Finally, the hippocampal volume was found to increase with the load of H-dPVS (p ¼ 0.005) after adjustment on the previously mentioned covariates. Each SD increase in the hippocampus volume was found associated with a higher risk of presenting more H-dPVS as compared with degree 0 (odds for degree 1 of H-dPVS: OR, 1.26; 95% CI, 1.08e1.47; for degree 2 of H-dPVS: OR, 1.23; 95% CI, 1.02e1.49). All these results remained significant even after adjustment for hypertension or use of anti-hypertensive drugs (data not shown). 3.4. Association between H-dPVS and baseline cognitive performance or incident dementia No significant relationship between the load of H-dPVS and baseline cognitive performance was observed in different multiple linear regression models (Table 4, all p > 0.05).
M. Yao et al. / Neurobiology of Aging xxx (2014) 1e8
5
Table 2 Potential risk factors by the load of dilated perivascular spaces in the hippocampus Distribution by load
Age, mean SD Male Hypertension Systolic blood pressure, mean (SD) Diastolic blood pressure, mean SD Use of antihypertensive drug Hypercholesterolemia Diabetes mellitus Ischemic heart disease Current smoking Current drinking apoE4 allele carrier
Degree 1 versus 0
Degree 2 versus 0
Degree 0 (n ¼ 1009)
Degree 1 (n ¼ 519)
Degree 2 (n ¼ 290)
OR (95% CI)
p
OR (95% CI)
p
72.24 4.10 40.9 73.5 147 (23) 84 (12) 39.3 57.5 7.9 8.1 6.4 81.1 23.7
72.64 4.22 36.4 78.8 149 (21) 86 (11) 43.5 54.4 8.7 7.5 5.0 77.9 19.6
72.88 4.09 35.9 84.5 153 (22) 86 (12) 53.1 58.3 9.0 9.0 5.9 80.0 20.1
1.1 0.83 1.35 1.13 1.18 1.16 0.85 1.13 0.92 0.81 0.86 0.80
0.08 0.09 0.021 0.037 0.004 0.19 0.13 0.53 0.7 0.38 0.27 0.10
1.16 0.81 1.98 1.34 1.28 1.68 1 1.17 1.11 0.97 0.98 0.83
0.022 0.13
Contents lists available at ScienceDirect
Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging
Hippocampal perivascular spaces are related to aging and blood pressure but not to cognition Ming Yao a, b, Yi-cheng Zhu a, Aïcha Soumaré c, d, Carole Dufouil c, d, Bernard Mazoyer e, f, g, h, i, Christophe Tzourio c, d, Hugues Chabriat b, j, k, * a
Department of Neurology, Peking Union Medical College Hospital, Beijing, China Univ Paris Diderot, Sorbonne Paris Cité, Paris, France Univ Pierre et Marie Curie Paris 6, Paris, France d INSERM UMR708, Bordeaux, France e Institut Universitaire de France, Paris, France f CNRS-CEA UMR 6232, Caen, France g Groupe Imagerie Neurofonctionelle, Caen, France h University Caen Basse-Normandie, Caen, France i CHU de Caen, Caen, France j INSERM UMR 1161 and DHU NeuroVasc, Paris, France k Department of Neurology, AP-HP, Paris, France b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 October 2013 Received in revised form 11 March 2014 Accepted 14 March 2014
The risk factors of hippocampal dilated perivascular spaces (H-dPVS), their radiological relevance and their impact on cognitive performance remain under investigation. These aspects were evaluated in 1818 stroke- and dementia-free participants enrolled in the 3C-Dijon MRI study, using logistic regression, multiple linear regression, and Cox models. At study entry, the load of H-dPVS was found strongly associated with age and hypertension (degree 2 vs. degree 0: odds ratio: 1.16; 95% confidence interval: 1.02e1.33 and odds ratio: 1.98; 95% confidence interval: 1.39e2.81, respectively) and positively related to the presence of lacunar infarcts, white-matter hyperintensities volume, and hippocampal volume (p 0.024). Load of H-dPVS was not related to baseline cognitive performance (p > 0.05). Cox regression modeling did not show a significant relationship between the load of H-dPVS and incident dementia risk (p > 0.05). The present results support that both aging and blood pressure do play a key role in the development of H-dPVS in the older population. In contrast with the dilated perivascular spaces located in white matter or basal ganglia, the load of H-dPVS does not appear associated with occurrence of dementia. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Hippocampal dilated perivascular spaces Risk factors MRI Cognition
1. Introduction Dilated perivascular spaces (dPVS) are commonly described from magnetic resonance imaging (MRI) in basal ganglia and in different subcortical white-matter regions (Chen et al., 2011; Cumurciuc et al., 2006; Groeschel et al., 2006; Maclullich et al., 2004; Patankar et al., 2005; Rouhl et al., 2008; Zhu et al., 2010a), while only a few studies have focused on hippocampal dilated perivascular spaces (H-dPVS) (Barboriak et al., 2000; Bartrés-Faz et al., 2001; Bastos-Leite et al., 2006; Chen et al., 2011; Li et al., 2006; Maclullich et al., 2004; Nakada et al., 2005; Sasaki et al., 1993; Yoneoka et al., 2002). The exact relationships between pathologic * Corresponding author at: Service de Neurologie, Hôpital Lariboisière, 2 rue Ambroise Paré, 75010 Paris, France. Tel.: þ33 1 49 95 25 93; fax: þ33 1 49 95 25 96. E-mail address: [email protected] (H. Chabriat). 0197-4580/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2014.03.021
data and the radiological aspects of H-dPVS as well as their exact clinical correlates are still debated. Various radiological terminologies, such as “cavities” or “sulcal cavities”, have been previously used for these lesions (Barboriak et al., 2000; Bartrés-Faz et al., 2001; Bastos-Leite et al., 2006; Li et al., 2006; Nakada et al., 2005; Sasaki et al., 1993; Yoneoka et al., 2002). However, histologic analyses strongly support that these “cavities” actually correspond to dilated cystic tissue remnants containing small perforating vessels and resulting from incomplete fusion of the hippocampus fissure during development (Sasaki et al., 1993). In the literature, the prevalence of H-dPVS seems to vary largely in healthy older populations (from 36.4% to 77%) (Barboriak et al., 2000; Li et al., 2006; Maclullich et al., 2004; Yoneoka et al., 2002). In most studies, a higher prevalence of H-dPVS is observed with aging (Barboriak et al., 2000; Sasaki et al., 1993; Yoneoka et al., 2002) although this was not confirmed by all authors (Chen et al., 2011; Li et al., 2006).
2
M. Yao et al. / Neurobiology of Aging xxx (2014) 1e8
In older individuals, the severity of dPVS in basal ganglia or white matter was recently found associated with an increased risk of cognitive decline or incident dementia (Maclullich et al., 2004; Zhu et al., 2010b). Since hippocampus plays a key role in memory performance (Frisoni et al., 2008; Lazarov et al., 2010; Sahay et al., 2011; Squire, 1992), the development of H-dPVS may be also related to cognitive performance in older people. However, their impact on cognition has been previously evaluated only in limited-samples and remains controversial. H-dPVS have been associated respectively with transient global amnesia or cognitive decline (Chen et al., 2011; Nakada et al., 2005). Conversely, other reports suggested that a higher number of hippocampal cerebrospinal fluid (CSF) spaces was not related to global cognitive performance (Bartrés-Faz et al., 2001; Maclullich et al., 2004) and was even possibly related to a lower risk of Alzheimer’s disease in a study of limited sample-size (Li et al., 2006). Otherwise, H-dPVS have not been found related to white-matter hyperintensities (WMH) (Barboriak et al., 2000; Chen et al., 2011), though the severity of dPVS in other cerebral areas has repeatedly shown to be a marker of cerebral small vessel disease (SVD) strongly related to the accumulation of lacunar infarcts, white-matter hyperintensities or microbleeds (Doubal et al., 2010; Patankar et al., 2005; Rouhl et al., 2008). In this study based on data collected in a large-sample of community-dwelling older individuals, we aimed at (1) investigating the risk factors of H-dPVS and their relationships with the other classical MRI markers of SVD; and (2) determining their impact on baseline cognitive performance or incident dementia over 8-years of follow-up. 2. Methods 2.1. Participants Data were obtained from the 3C-Dijon MRI study, a cohort study of community-dwelling persons aged 65 years and older, randomly selected from the electoral rolls in the city of Dijon France. The complete study protocol, approved by the Ethical Committee of the University-Hospital of Bicêtre, has been detailed elsewhere (3C Study Group, 2003). All participants gave a signed informed consent. Among the 4931 participants included in Dijon, those 0.05). In preliminary analyses, we observed that age, APOE genotype, and depressive symptoms were the strongest predictors of dementia among the potential studied risk factors, while education level, age, depressive symptoms, gender, and number of cardiovascular diseases or risk factors were associated with cognition (at least 1 cognitive test) (data not shown). Multiple linear regression models (dependent variables ¼ each baseline cognitive score) and Cox proportional hazard models were performed to evaluate the relationships between the severity of H-dPVS and different baseline cognitive performance or incident dementia. Because cognitive tests scores were not normally distributed, they were logtransformed. Analyses for association between the severity of HdPVS and cognition or dementia were performed in 3 steps. First, age, gender, and education level were controlled (model 1). A preliminary search for potential interaction between H-dPVS and age, gender, or education level in relation to the different outcomes (cognitive function and dementia) was performed, but none was significant. Second, models were further adjusted for covariates that were associated with dementia, cognition (at least 1 cognitive test) or for covariates known to be risk factors for dementia or cognitive function, that is, APOE genotype, depressive symptoms, and number of cardiovascular diseases or risk factors (model 2). Third, to assess whether other brain lesions or cerebral atrophy could modify the association between H-dPVS and cognitive performance or incident dementia, additional adjustments for WMH volume, the presence and/or the absence of brain infarcts, and brain parenchymal fraction were obtained (model 3). Statistical analyses were performed using SPSS version 20.0 for Windows (SPSS Inc). All p-values were 2-tailed and criteria for significance were p < 0.05. 3. Results 3.1. Baseline characteristics The demographic, clinical, and main MRI features at baseline are summarized in Table 1. The mean age of participants was 72.46 years (SD ¼ 4.14), 38.8% (n ¼ 706) participants were men. Regarding H-dPVS, 44.5% of individuals had at least 1 H-dPVS with a maximum number of 10. 3.2. Risk factors of H-dPVS As shown in Table 2, the load of H-dPVS increased with age; each SD increase in age was associated with a higher odds of H-dPVS (for degree 2 vs. degree 0: odds ratio [OR] 1.16; 95% confidence interval [CI]: 1.02e1.33, p ¼ 0.022). Comparison of degree 1 and degree 0 resulted in a similar but nonsignificant trend (p ¼ 0.08). After adjustment for age and gender, the load of H-dPVS was found to increase both with systolic and with diastolic blood pressure (p 0.037). Baseline hypertension was also associated with H-dPVS with a doubling of the adjusted odds when degree 2 was compared with degree 0 (p < 0.001). No interaction was detected between age and blood pressure on the load of H-dPVS. HdPVS of degree 2 was also significantly related to the use of antihypertensive drugs (p < 0.001). In contrast, the load of H-dPVS was not found related to gender, smoking or drinking status,
Table 1 Main characteristics of the cohort (N ¼ 1818) Characteristics Age (y), mean SD (range) Male gender Hypertension Hypercholesterolemia Diabetes Ischemic heart disease Current smoker Current drinker Apolipoprotein E4 allele carrier Cognitive scores Mini-Mental State Examination score, mean SD BENTON visual, mean SD Isaacs set test, mean SD Trail making tests part A, mean SD Trail making tests part B, mean SD MRI markers Absolute volume of WMH in cm3, mean SD Presence of lacunar infarcts Absolute volume of gray matter in cm3, mean SD Absolute volume of hippocampus in cm3, mean SD BPF, mean SD Number of H-dPVS 0 1e2 >2
72.46 4.14 (65e85) 38.8% (706) 76.8% (1396) 56.8% (1025) 8.3% (150) 8.1% (147) 5.9% (108) 80.0% (1450) 22.0% (396) 27.67 1.87 11.73 1.91 34.07 6.73 2.22 0.83 6.69 8.44 5.54 5.04 6.8% (121) 508.18 51.03 6.61 0.85 71.82 3.2 55.5% (1009) 28.5% (519) 16.0% (290)
Key: BPF, brain parenchymal fraction; H-dPVS, dilated perivascular spaces in hippocampus; MRI, magnetic resonance imaging; SD, standard deviation; WMH, whitematter hyperintensities.
hypercholesterolemia, diabetes, ischemic heart disease, or APOE4 genotype. 3.3. Relationships between the severity of H-dPVS and the other MRI markers of SVD As shown in Table 3, participants with H-dPVS of degree 2 had the highest prevalence of lacunar infarcts and the highest volume of WMH, deep WMH, and perivascular WMH, whereas the contrary was found for those with degree 0. After adjustment for age, gender, and total intracranial volume, degree 2 of H-dPVS (vs. degree 0) was found strongly related to the total WMH volume (p < 0.001,OR: 1.34; 95% CI: 1.19e1.51). Degree 2 of H-dPVS was also found significantly related both to the volume of deep WMH and to that of perivascular WMH (p < 0.001), and associated with the presence of lacunar infarcts (p ¼ 0.007). Conversely, no significant association was detected for degree 1 neither with the WMH volume (p ¼ 0.11) nor with the presence of lacunar infarcts (p ¼ 0.12) although a similar trend was detected. Finally, the hippocampal volume was found to increase with the load of H-dPVS (p ¼ 0.005) after adjustment on the previously mentioned covariates. Each SD increase in the hippocampus volume was found associated with a higher risk of presenting more H-dPVS as compared with degree 0 (odds for degree 1 of H-dPVS: OR, 1.26; 95% CI, 1.08e1.47; for degree 2 of H-dPVS: OR, 1.23; 95% CI, 1.02e1.49). All these results remained significant even after adjustment for hypertension or use of anti-hypertensive drugs (data not shown). 3.4. Association between H-dPVS and baseline cognitive performance or incident dementia No significant relationship between the load of H-dPVS and baseline cognitive performance was observed in different multiple linear regression models (Table 4, all p > 0.05).
M. Yao et al. / Neurobiology of Aging xxx (2014) 1e8
5
Table 2 Potential risk factors by the load of dilated perivascular spaces in the hippocampus Distribution by load
Age, mean SD Male Hypertension Systolic blood pressure, mean (SD) Diastolic blood pressure, mean SD Use of antihypertensive drug Hypercholesterolemia Diabetes mellitus Ischemic heart disease Current smoking Current drinking apoE4 allele carrier
Degree 1 versus 0
Degree 2 versus 0
Degree 0 (n ¼ 1009)
Degree 1 (n ¼ 519)
Degree 2 (n ¼ 290)
OR (95% CI)
p
OR (95% CI)
p
72.24 4.10 40.9 73.5 147 (23) 84 (12) 39.3 57.5 7.9 8.1 6.4 81.1 23.7
72.64 4.22 36.4 78.8 149 (21) 86 (11) 43.5 54.4 8.7 7.5 5.0 77.9 19.6
72.88 4.09 35.9 84.5 153 (22) 86 (12) 53.1 58.3 9.0 9.0 5.9 80.0 20.1
1.1 0.83 1.35 1.13 1.18 1.16 0.85 1.13 0.92 0.81 0.86 0.80
0.08 0.09 0.021 0.037 0.004 0.19 0.13 0.53 0.7 0.38 0.27 0.10
1.16 0.81 1.98 1.34 1.28 1.68 1 1.17 1.11 0.97 0.98 0.83
0.022 0.13
