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Cerebrovascular lesions in elderly Japanese patients with Alzheimer's disease
Journal of the Neurological Sciences 322 (2012) 87–91
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Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Cerebrovascular lesions in elderly Japanese patients with Alzheimer's disease Ken Nagata ⁎, Daiki Takano, Takashi Yamazaki, Tetsuya Maeda, Yuichi Satoh, Taizen Nakase, Yasuko Ikeda Department of Neurology, Research Institute for Brian and Blood Vessels, Japan
a r t i c l e
i n f o
Article history: Received 9 February 2012 Received in revised form 10 June 2012 Accepted 2 July 2012 Available online 3 August 2012 Keywords: Cerebrovascular lesions Lacunar infarction White matter lesions Microbleeds Thalamusvascular risk factors
a b s t r a c t Objective: Cerebrovascular lesions (CVLs) are known to play important roles in the pathophysiology underlying Alzheimer's disease (AD), especially in elderly AD cases. The present study was conducted to elucidate the relationship between the CVLs and vascular risk factors (VRFs) in elderly Japanese patients with AD. Subjects and methods: The CVLs such as lacunar infarcts, old microbleeds (OMBs), white matter lesions (WMLs), and occlusive vascular lesions on MRI were analyzed in relation to the risk factors in 120 Japanese patients with probable AD. Their mean age was 75.6 years. The subjects were divided into two age groups: young-old group (YOG) consisting of 55 cases being younger than 75 years and old-old group (OOG) consisting of 65 cases being 75 years or older. Results: In overall analysis, 10 cases (8.3%) showed brain atrophy without CVLs on MRI, 46 cases (38.3%) showed WMLs in addition to the brain atrophy, 61 cases (50.8%) showed lacunar lesions, and 3 cases (2.5%) were diagnosed as having a superficial siderosis. Lacunar infarcts and OMBs were more frequently observed in OOG than in YOG, and were also more frequently observed in those with 2 or more VRFs than those with less than 2 VRFs (pb 0.05). The WMLs were more pronounced in OOG, and in those with more VRFs. Conclusion: The CVLs including lacunes, WMLs, and OMBs were present more than 90% of elderly Japanese patients with AD. As the severity of CVLs was associated with VRFs and age, VRFs may modify clinical presentation of elderly AD patients. © 2012 Published by Elsevier B.V.
1. Introduction Since the Nun Study [1] showed that cerebrovascular lesions (CVLs) were closely associated with the presence and severity of clinical symptoms in Alzheimer's disease (AD), CVLs have been drawing attention in understanding the pathophysiology underlying AD patients, especially elderly AD cases [2–4]. The risk factors concerning dementia can be classified into 4 categories: genetic, demographic, vascular, and strokerelated risk factors. Aging, low educational level and history of head trauma are included in the demographic risk factors. Although the mechanisms by which those risk factors increase the risk of AD and accelerate cognitive decline among AD patients are not yet fully understood, hypertension in midlife, type 2 diabetes, dyslipidemia, congestive heart failure, smoking habit, metabolic syndrome, hyperhomocysteinemia, and hypotension in late life are now considered as vascular risk factors (VRFs) for AD as well as for stroke. Occurrence of stroke is known to accelerate cognitive deterioration not only in patients with vascular dementia (VaD) but also among AD patients. Lacunar infarction, white matter lesions (WMLs), microbleeds, strategic lesions, volume of the brain tissue loss and occlusive vascular lesions are included in the stroke-related risk factors [5–9].
⁎ Corresponding author at: Department of Neurology, Research Institute for Brain and Blood Vessels, 6–10 Senshu-Kubota-Machi Akita 010–0874, Japan. Tel.: +81 188 33 0115; fax: +81 188 33 6006. E-mail address: [email protected] (K. Nagata). 0022-510X/$ – see front matter © 2012 Published by Elsevier B.V. doi:10.1016/j.jns.2012.07.001
Although there are many literature in which VRFs and CVLs were compared in a large number of Caucasian subjects with AD, only a few reports analyzed the relationship between the VRF and CVLs in Japanese AD patients [10,11]. The present study was conducted to elucidate the relationship between the CVLs on MRI and VRFs in elderly Japanese patients with AD. 2. Subjects and methods The present study was based on 120 Japanese patients (41 men and 79 women) who were diagnosed as having probable AD cases according to the NINCDS-ADRDA criteria [12]. Their mean age was 75.6 years. All subjects underwent 1.5 Tesla MRI including T1 weighted images (T1WI), T2 weighted images (T2WI), echo-planar gradient-echo T2* weighted images (T2*WI), fluid attenuated inversion recovery (FLAIR) and MR angiography (MRA). Evaluation of lacunar lesion was done on T2WI and the existence of the old microbleeds (OMBs) was evaluated on T2*WI. The severity of white matter lesions was evaluated on FLAIR images according to Fazekas' classification [13]. Neuropsychological evaluation included mini-mental state exam (MMSE) and clock drawing test (CDT). Laboratory blood studies included fibrinogen, D-dimer, lipid profile, fasting plasma glucose, serum insulin, brain natriuretic peptide and APOE phenotyping. Vascular risk factors (VRFs) were identified using self-report and laboratory findings: hypertension, hypercholesterolemia, diabetes mellitus, current smoking, atrial fibrillation, congestive heart failure, chronic kidney disease, history of
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Fig. 3. Mean MMSE score according to the number of vascular risk factors. Fig. 1. Number of vascular risk factors (VRFs) in overall analysis.
vascular disease. The VRFs were dichotomized as present or absent according to the published guidelines. Participants having a history of stroke events were excluded from the analysis. According to their age, the subjects were divided into two age groups: young-old group (YOG) consisting of 55 cases who were 75 years or younger and old-old group (OOG) consisting of 65 cases who were 76 years or older. Group differences at baseline were assessed using Student t test, and Mann–Whitney U test, and χ2 or Fisher exact test where appropriate.
3. Results In the overall analysis, 5 cases (4.2%) had no VRF, 17 cases (14.2%) had 1 VRF, 46 cases (38.3%) had 2 VRFs, 37 cases (30.8%) had 3 VRFs and 15 cases (12.5%) had 4 VRFs (Fig. 1). Four cases (7.3%) had no VRF, 8 cases (14.5%) had 1 VRF, 22 cases (40.0%) had 2 VRFs, 15 cases (27.3%) had 3 VRFs and 6 cases (10.9%) had 4 VRFs in YOG, whereas 1 case (1.5%) had no VRF, 9 cases (12.3%) had 1 VRF, 24 cases (36.9%) had 2 VRFs, 23 cases (35.5%) had 3 VRFs and 15 cases (13.8%) had 4 VRFs in OOG (Fig. 2). Although there was no statistical significance, there was a tendency toward the OOG to have more VRF2 as compared with YOG.
The mean scores for MMSE and CDT were 19.1 and 3.4, respectively. The mean MMSE score did not differ according to the number of VRFs (Fig. 3). Sixty-nine cases (57.5%) had APOE4, and 12 cases (10.0%) had homozygous APOE4. The possession of APOE4 did not differ between YOG and OOG. In the overall analysis, 10 cases (8.3%) showed brain atrophy without CVLs on MRI, 46 cases (38.3%) showed WMLs in addition to brain atrophy, 61 cases (50.8%) showed lacunar infarcts, and 3 cases (2.5%) were diagnosed as having a superficial siderosis (Fig. 4). Forty-three cases (66.2%) showed lacunar infarcts in OOG whereas only 18 cases (32.7%) showed lacunar infarcts in YOG (Fig. 5). Lacunar infarcts were more frequently observed in OOG than in YOG (pb 0.05). Lacunar infarcts were detected in 54 cases (54.5%) who had less than 2 VRFs, whereas those were observed in 7 (33.3%) of 21 cases who had 2 or more VRFs (Fig. 6). Lacunar infarcts were more frequently observed in those with 2 or more VRFs than those with less than 2 VRFs (pb 0.05). Thalamic lacunar infarcts were detected in 18 cases (15.0%) and basal ganglionic lacunar lesions were detected in 64 cases (54.2%). The mean MMSE score was 16.8 in those with thalamic lacunar infarcts, whereas that was 19.5 in those without thalamic lacunar infarcts. The OMBs were detected in 21 cases (17.5%) in overall analysis. Seven cases (12.7%) showed OMBs in YOG, whereas 14 cases (21.5%) showed OMB in OOG. The OMBs were more frequently detected in
Fig. 2. Number of vascular risk factors (VRFs) in YOG and OOG.
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The occlusive vascular lesions were detected in 4 cases (7.3%) in YOG whereas those lesions were observed in 13 cases (20.0%) in OOG. The occlusive vascular lesions were detected in only 1 case (4.8%) in those with less than 2 VRFs, whereas those lesions were detected in 16 cases (16.2%) in those with 2 or more VRFs. The occlusive vascular lesions were more frequently observed in older subjects and in those with more VRFs (pb 0.05).
4. Discussion
Fig. 4. MRI findings in overall analysis.
OOG than YOG (pb 0.05). The OMBs were detected in 3 (14.3%) of 21 cases having less than 2 VRF2, whereas those were detected in 18 (18.8%) of 99 cases having 2 or more VRFs. The OMBs were more frequently detected in those with 2 or more VRFs (pb 0.05). The OMBs were detected in 13 (17.5%) of 51cases with APOE4, whereas those were seen in 7 (10.1%) of 69 cases without APOE4. The severity of WMLs was evaluated as Grade 0 in 13 cases (10.8%), Grade 1 in 62 cases (51.7%), Grade 2 in 36 cases (30.0%), and Grade 3 in 9 cases (7.5%) in the overall analysis. As shown in Fig. 7, the severity of WMLs was evaluated as Grade 2 in 15 cases (27.3%) and Grade 3 in 3 cases (5.5%) in YOG, whereas that was evaluated as Grade 2 in 21 cases (32.2%) and Grade 3 in 6 cases (9.2%) in OOG. The WMLs were more pronounced in OOG than in YOG. The severity of WMLs was evaluated as Grade 2 in 14 cases (23.8%) and Grade 3 in 1 case (4.8%) in those having less than 2 VRFs, whereas that was evaluated as Grade 2 in 32 cases (32.3%) and Grade 3 in 8 cases (8.1%) in those having 2 or more VRFs (Fig. 8). The WMLs were more pronounced in those having more VRFs. The mean MMSE score did not differ significantly according to the grade of WMLs (Fig. 9). On MR-angiography, the occlusive vascular lesions were detected in the intracranial major arteries in 17 cases (14.2%) in overall analysis.
In the results, the small-vessel lesions such as lacunar infarcts, OMBs and WMLs were observed in more than 90% of elderly Japanese patients with AD, and they appeared more frequently in the older subjects. Although the epidemiological studies showed that the incidence of intracerebral hemorrhage was significantly higher in Asian subjects than in white, Hispanic or black population [14], the presentation of OMBs was not so frequent in Japanese AD patients as compared with European subjects [15]. The CVLs were more frequently detected in the older age group (OOG) than in the younger age group (YOG). It was suggested that CVLs were associated with increasing age, and the concomitant CVLs may modify the clinical manifestations in elderly AD patients. The CVLs were also more frequently seen in those with more VRFs than in those with less VRFs in our results. This may indicate a close relationship between the vascular risk factors and CVLs in the elderly AD patients. Previous clinical studies have documented a close relationship between CVLs and risk of AD. Most of those factors have been shown to be associated with subcortical small-vessel lesions detected on MRI such as lacunar infarction [16–19], WMLs [20–23], and old microbleeds [24–32]. Clinical significance of lacunar infarcts has been suggested in previous clinicopathological and epidemiological studies [1–3]. Even silent small infarcts are considered to be a risk for subsequent stroke as well as cognitive deterioration in dementia. Although the exact mechanisms concerning the role of small vessel lesions in clinical manifestation of dementia are not yet fully explained, the disconnection of the subcortical network can be a candidate for the possible cause of cognitive deterioration in elderly AD patients. The OMBs were more frequently detected in those with APOE4 in our results, and this may imply an association with underlying cerebral amyloid angiopathy (CAA). In previous reports, OMBs have
Fig. 5. MRI findings in YOG and OOG.
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Fig. 6. MRI findings in those with less than 2 VRFs and those with 2 or more VRFs.
Fig. 7. Grade of white matter lesions in YOG and OOG.
Fig. 8. Grade of white matter lesions in those with less than 2 VRFs and those with 2 or more VRFs.
K. Nagata et al. / Journal of the Neurological Sciences 322 (2012) 87–91
Fig. 9. Mean MMSE scores according to the grade of white matter lesions.
been associated with increasing age [24–27], lacunar infarcts and white matter lesions [24,27,28], hypertension [24–27], diabetes mellitus [26], smoking [24,27], and APOE 4 alleles [24]. Lobar or cortical OMBs are usually attributed to the CAA, whereas subcortical or basal ganglionic OMBs are generally associated with VRFs such as hypertension [29–31]. Ischemic cerebrovascular lesions are considered to enhance the severity of cognitive impairment in AD patients. Regardless of symptomatic or silent lesions, the subcortical small lesions such as thalamic and basal ganglia lacunar infarcts are considered to have greater impact on the cognitive ability in patients with AD pathology, and to accelerate the tempo of cognitive decline. Those effects of CVLs are more pronounced in patients in the early stages of AD. Therefore, the coexisting CVLs may accelerate disease progression in elderly AD patients. As the severity of CVLs was associated with increasing age and number of VRF in our results, the strict management of those VRFs is prerequisite in the prevention and treatment of elderly AD patients. Reference [1] Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA 1997;277:813–7. [2] Esiri MM, Nagy Z, Smith MZ, Barnetson L, Smith AD. Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer's disease. Lancet 1999;354:919–20. [3] Lee JH, Olichney JM, Hansen LA, Hofstetter CR, Thal LJ. Small concomitant vascular lesions do not influence rates of cognitive decline in patients with Alzheimer disease. Arch Neurol 2000;57:1474–9. [4] Zekry D, Duyckaerts C, Moulias R, Belmin J, Geoffre C, Herrmann F, et al. Degenerative and vascular lesions of the brain have synergistic effects in dementia of the elderly. Acta Neuropathol (Berl) 2002;103:481–7. [5] Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, et al. Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study. BMJ 2001;322:1447–51. [6] Hofman A, Ott A, Breteler MM, Bots ML, Slooter AJ, van Harskamp F, et al. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study. Lancet 1997;349:151–4. [7] Skoog I, Lernfelt B, Landahl S, Palmertz B, Andreasson LA, Nilsson L, et al. 15-year longitudinal study of blood pressure and dementia. Lancet 1996;347:1141–5. [8] Chui HC, Zarow C, Mack WJ, Ellis WG, Zheng L, Jagust WJ, et al. Cognitive impact of subcortical vascular and Alzheimer's disease pathology. Ann Neurol 2006;60:677–87. [9] Biessels GJ, Deary IJ, Ryan CM. Cognition and diabetes: a lifespan perspective. Lancet Neurol 2008;7:184–90. [10] Hanyu H, Nakano S, Abe S, Arai H, Iwamoto T, Takasaki M. Differential diagnosis of Alzheimer-type dementia and vascular dementia based on neuroimaging study. No To Shinkei 1995;47:665–70.
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[11] Hanyu H, Nakano S, Abe S, Arai H, Iwamoto T, Takasaki M. Differences of neuroimaging between early-onset and late-onset Alzheimer-type dementia. Rinsho Shinkeigaku 1995;35:1104–9. [12] McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34:939–44. [13] Fazekas F, Niederkorn K, Schmidt R, Offenbacher H, Horner S, Bertha G, et al. White matter signal abnormalities in normal individuals: correlation with carotid ultrasonography, cerebral blood flow measurements, and cerebrovascular risk factors. Stroke 1988;19:1285–8. [14] van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol 2010;9:167–76. [15] Yates PA, Sirisriro R, Villemagne VL, Farquharson S, Masters CL, Rowe CC. AIBL Research Group: cerebral microhemorrhage and brain β-amyloid in aging and Alzheimer disease. Neurology 2011;77:48–54. [16] Bernick C, Kuller L, Dulberg C, Longstreth Jr WT, Manolio T, Beauchamp N, et al. Cardiovascular Health Study Collaborative Reseach Group: silent MRI infarcts and the risk of future stroke: the cardiovascular health study. Neurology 2001;57:1222–9. [17] Gold G, Kövari E, Herrmann FR, Canuto A, Hof PR, Michel JP, et al. Cognitive consequences of thalamic, basal ganglia, and deep white matter lacunes in brain aging and dementia. Stroke 2005;36:1184–8. [18] Benisty S, Gouw AA, Porcher R, Madureira S, Hernandez K, Poggesi A, et al. Location of lacunar infarcts correlates with cognition in a sample of non-disabled subjects with age-related white-matter changes: the LADIS study. J Neurol Neurosurg Psychiatry 2009;80:478–83. [19] Strozyk D, Dickson DW, Lipton RB, Katz M, Derby CA, Lee S, et al. Contribution of vascular pathology to the clinical expression of dementia. Neurobiol Aging 2010;31:1710–20. [20] Liao D, Cooper L, Cai J, Toole J, Bryan N, Burke G, et al. The prevalence and severity of white matter lesions, their relationship with age, ethnicity, gender, and cardiovascular disease risk factors: The ARIC study. Neuroepidemiology 1997;16: 149–62. [21] Longstreth Jr WT, Manolio TA, Arnold A, Burke GL, Bryan N, Jungreis CA, et al. Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people: the cardiovascular health study. Stroke 1996;27:1274–82. [22] Longstreth Jr WT, Manolio TA, Arnold A, Burke GL, Bryan N, Jungreis CA, et al. Progression of cerebral white matter hyperintensities on MRI is related to diastolic blood pressure. Neurology 1998;51:319–20. [23] Carmichael O, Schwarz C, Drucker D, Fletcher E, Harvey D, Beckett L, et al. Alzheimer's Disease Neuroimaging Initiative: longitudinal changes in white matter disease and cognition in the first year of the Alzheimer disease neuroimaging initiative. Arch Neurol 2010;67:1370–8. [24] Viswanathan A, Chabriat H. Cerebral microhemorrhage. Stroke 2006;37:550–5. [25] Poels MM, Vernooij MW, Ikram MA, Hofman A, Krestin GP, van der Lugt A, et al. Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam scan study. Stroke 2010;41:S103–6. [26] Jeerakathil T, Wolf PA, Beiser A, Hald JK, Au R, Kase CS, et al. Cerebral microbleeds: prevalence and associations with cardiovascular risk factors in the Framingham Study. Stroke 2004;35:1831–5. [27] Roob G, Schmidt R, Kapeller P, Lechner A, Hartung HP, Fazekas F. MRI evidence of past cerebral microbleeds in a healthy elderly population. Neurology 1999;52: 991–4. [28] Tsushima Y, Tanizaki Y, Aoki J, Endo K. MR detection of microhemorrhages in neurologically healthy adults. Neuroradiology 2002;44:31–6. [29] Goos JD, Henneman WJ, Sluimer JD, Vrenken H, Sluimer IC, Barkhof F, et al. Incidence of cerebral microbleeds. Neurology 2010;74:1954–60. [30] Pettersen JA, Sathiyamoorthy G, Gao FQ, Szilagyi G, Nadkarni NK, St GeorgeHyslop P, et al. Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study. Arch Neurol 2008;65: 790–5. [31] Greenberg SM, Vernooij MW, Cordonnier C, Viswanathan A, Al-Shahi Salman R, Warach S, et al. Microbleed Study Group: cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 2009;8:165–74. [32] Vernooij MW, van der Lugt A, Ikram MA, Wielopolski PA, Niessen WJ, Hofman A, et al. Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurology 2008;70:1208–14.
Contents lists available at SciVerse ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Cerebrovascular lesions in elderly Japanese patients with Alzheimer's disease Ken Nagata ⁎, Daiki Takano, Takashi Yamazaki, Tetsuya Maeda, Yuichi Satoh, Taizen Nakase, Yasuko Ikeda Department of Neurology, Research Institute for Brian and Blood Vessels, Japan
a r t i c l e
i n f o
Article history: Received 9 February 2012 Received in revised form 10 June 2012 Accepted 2 July 2012 Available online 3 August 2012 Keywords: Cerebrovascular lesions Lacunar infarction White matter lesions Microbleeds Thalamusvascular risk factors
a b s t r a c t Objective: Cerebrovascular lesions (CVLs) are known to play important roles in the pathophysiology underlying Alzheimer's disease (AD), especially in elderly AD cases. The present study was conducted to elucidate the relationship between the CVLs and vascular risk factors (VRFs) in elderly Japanese patients with AD. Subjects and methods: The CVLs such as lacunar infarcts, old microbleeds (OMBs), white matter lesions (WMLs), and occlusive vascular lesions on MRI were analyzed in relation to the risk factors in 120 Japanese patients with probable AD. Their mean age was 75.6 years. The subjects were divided into two age groups: young-old group (YOG) consisting of 55 cases being younger than 75 years and old-old group (OOG) consisting of 65 cases being 75 years or older. Results: In overall analysis, 10 cases (8.3%) showed brain atrophy without CVLs on MRI, 46 cases (38.3%) showed WMLs in addition to the brain atrophy, 61 cases (50.8%) showed lacunar lesions, and 3 cases (2.5%) were diagnosed as having a superficial siderosis. Lacunar infarcts and OMBs were more frequently observed in OOG than in YOG, and were also more frequently observed in those with 2 or more VRFs than those with less than 2 VRFs (pb 0.05). The WMLs were more pronounced in OOG, and in those with more VRFs. Conclusion: The CVLs including lacunes, WMLs, and OMBs were present more than 90% of elderly Japanese patients with AD. As the severity of CVLs was associated with VRFs and age, VRFs may modify clinical presentation of elderly AD patients. © 2012 Published by Elsevier B.V.
1. Introduction Since the Nun Study [1] showed that cerebrovascular lesions (CVLs) were closely associated with the presence and severity of clinical symptoms in Alzheimer's disease (AD), CVLs have been drawing attention in understanding the pathophysiology underlying AD patients, especially elderly AD cases [2–4]. The risk factors concerning dementia can be classified into 4 categories: genetic, demographic, vascular, and strokerelated risk factors. Aging, low educational level and history of head trauma are included in the demographic risk factors. Although the mechanisms by which those risk factors increase the risk of AD and accelerate cognitive decline among AD patients are not yet fully understood, hypertension in midlife, type 2 diabetes, dyslipidemia, congestive heart failure, smoking habit, metabolic syndrome, hyperhomocysteinemia, and hypotension in late life are now considered as vascular risk factors (VRFs) for AD as well as for stroke. Occurrence of stroke is known to accelerate cognitive deterioration not only in patients with vascular dementia (VaD) but also among AD patients. Lacunar infarction, white matter lesions (WMLs), microbleeds, strategic lesions, volume of the brain tissue loss and occlusive vascular lesions are included in the stroke-related risk factors [5–9].
⁎ Corresponding author at: Department of Neurology, Research Institute for Brain and Blood Vessels, 6–10 Senshu-Kubota-Machi Akita 010–0874, Japan. Tel.: +81 188 33 0115; fax: +81 188 33 6006. E-mail address: [email protected] (K. Nagata). 0022-510X/$ – see front matter © 2012 Published by Elsevier B.V. doi:10.1016/j.jns.2012.07.001
Although there are many literature in which VRFs and CVLs were compared in a large number of Caucasian subjects with AD, only a few reports analyzed the relationship between the VRF and CVLs in Japanese AD patients [10,11]. The present study was conducted to elucidate the relationship between the CVLs on MRI and VRFs in elderly Japanese patients with AD. 2. Subjects and methods The present study was based on 120 Japanese patients (41 men and 79 women) who were diagnosed as having probable AD cases according to the NINCDS-ADRDA criteria [12]. Their mean age was 75.6 years. All subjects underwent 1.5 Tesla MRI including T1 weighted images (T1WI), T2 weighted images (T2WI), echo-planar gradient-echo T2* weighted images (T2*WI), fluid attenuated inversion recovery (FLAIR) and MR angiography (MRA). Evaluation of lacunar lesion was done on T2WI and the existence of the old microbleeds (OMBs) was evaluated on T2*WI. The severity of white matter lesions was evaluated on FLAIR images according to Fazekas' classification [13]. Neuropsychological evaluation included mini-mental state exam (MMSE) and clock drawing test (CDT). Laboratory blood studies included fibrinogen, D-dimer, lipid profile, fasting plasma glucose, serum insulin, brain natriuretic peptide and APOE phenotyping. Vascular risk factors (VRFs) were identified using self-report and laboratory findings: hypertension, hypercholesterolemia, diabetes mellitus, current smoking, atrial fibrillation, congestive heart failure, chronic kidney disease, history of
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Fig. 3. Mean MMSE score according to the number of vascular risk factors. Fig. 1. Number of vascular risk factors (VRFs) in overall analysis.
vascular disease. The VRFs were dichotomized as present or absent according to the published guidelines. Participants having a history of stroke events were excluded from the analysis. According to their age, the subjects were divided into two age groups: young-old group (YOG) consisting of 55 cases who were 75 years or younger and old-old group (OOG) consisting of 65 cases who were 76 years or older. Group differences at baseline were assessed using Student t test, and Mann–Whitney U test, and χ2 or Fisher exact test where appropriate.
3. Results In the overall analysis, 5 cases (4.2%) had no VRF, 17 cases (14.2%) had 1 VRF, 46 cases (38.3%) had 2 VRFs, 37 cases (30.8%) had 3 VRFs and 15 cases (12.5%) had 4 VRFs (Fig. 1). Four cases (7.3%) had no VRF, 8 cases (14.5%) had 1 VRF, 22 cases (40.0%) had 2 VRFs, 15 cases (27.3%) had 3 VRFs and 6 cases (10.9%) had 4 VRFs in YOG, whereas 1 case (1.5%) had no VRF, 9 cases (12.3%) had 1 VRF, 24 cases (36.9%) had 2 VRFs, 23 cases (35.5%) had 3 VRFs and 15 cases (13.8%) had 4 VRFs in OOG (Fig. 2). Although there was no statistical significance, there was a tendency toward the OOG to have more VRF2 as compared with YOG.
The mean scores for MMSE and CDT were 19.1 and 3.4, respectively. The mean MMSE score did not differ according to the number of VRFs (Fig. 3). Sixty-nine cases (57.5%) had APOE4, and 12 cases (10.0%) had homozygous APOE4. The possession of APOE4 did not differ between YOG and OOG. In the overall analysis, 10 cases (8.3%) showed brain atrophy without CVLs on MRI, 46 cases (38.3%) showed WMLs in addition to brain atrophy, 61 cases (50.8%) showed lacunar infarcts, and 3 cases (2.5%) were diagnosed as having a superficial siderosis (Fig. 4). Forty-three cases (66.2%) showed lacunar infarcts in OOG whereas only 18 cases (32.7%) showed lacunar infarcts in YOG (Fig. 5). Lacunar infarcts were more frequently observed in OOG than in YOG (pb 0.05). Lacunar infarcts were detected in 54 cases (54.5%) who had less than 2 VRFs, whereas those were observed in 7 (33.3%) of 21 cases who had 2 or more VRFs (Fig. 6). Lacunar infarcts were more frequently observed in those with 2 or more VRFs than those with less than 2 VRFs (pb 0.05). Thalamic lacunar infarcts were detected in 18 cases (15.0%) and basal ganglionic lacunar lesions were detected in 64 cases (54.2%). The mean MMSE score was 16.8 in those with thalamic lacunar infarcts, whereas that was 19.5 in those without thalamic lacunar infarcts. The OMBs were detected in 21 cases (17.5%) in overall analysis. Seven cases (12.7%) showed OMBs in YOG, whereas 14 cases (21.5%) showed OMB in OOG. The OMBs were more frequently detected in
Fig. 2. Number of vascular risk factors (VRFs) in YOG and OOG.
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The occlusive vascular lesions were detected in 4 cases (7.3%) in YOG whereas those lesions were observed in 13 cases (20.0%) in OOG. The occlusive vascular lesions were detected in only 1 case (4.8%) in those with less than 2 VRFs, whereas those lesions were detected in 16 cases (16.2%) in those with 2 or more VRFs. The occlusive vascular lesions were more frequently observed in older subjects and in those with more VRFs (pb 0.05).
4. Discussion
Fig. 4. MRI findings in overall analysis.
OOG than YOG (pb 0.05). The OMBs were detected in 3 (14.3%) of 21 cases having less than 2 VRF2, whereas those were detected in 18 (18.8%) of 99 cases having 2 or more VRFs. The OMBs were more frequently detected in those with 2 or more VRFs (pb 0.05). The OMBs were detected in 13 (17.5%) of 51cases with APOE4, whereas those were seen in 7 (10.1%) of 69 cases without APOE4. The severity of WMLs was evaluated as Grade 0 in 13 cases (10.8%), Grade 1 in 62 cases (51.7%), Grade 2 in 36 cases (30.0%), and Grade 3 in 9 cases (7.5%) in the overall analysis. As shown in Fig. 7, the severity of WMLs was evaluated as Grade 2 in 15 cases (27.3%) and Grade 3 in 3 cases (5.5%) in YOG, whereas that was evaluated as Grade 2 in 21 cases (32.2%) and Grade 3 in 6 cases (9.2%) in OOG. The WMLs were more pronounced in OOG than in YOG. The severity of WMLs was evaluated as Grade 2 in 14 cases (23.8%) and Grade 3 in 1 case (4.8%) in those having less than 2 VRFs, whereas that was evaluated as Grade 2 in 32 cases (32.3%) and Grade 3 in 8 cases (8.1%) in those having 2 or more VRFs (Fig. 8). The WMLs were more pronounced in those having more VRFs. The mean MMSE score did not differ significantly according to the grade of WMLs (Fig. 9). On MR-angiography, the occlusive vascular lesions were detected in the intracranial major arteries in 17 cases (14.2%) in overall analysis.
In the results, the small-vessel lesions such as lacunar infarcts, OMBs and WMLs were observed in more than 90% of elderly Japanese patients with AD, and they appeared more frequently in the older subjects. Although the epidemiological studies showed that the incidence of intracerebral hemorrhage was significantly higher in Asian subjects than in white, Hispanic or black population [14], the presentation of OMBs was not so frequent in Japanese AD patients as compared with European subjects [15]. The CVLs were more frequently detected in the older age group (OOG) than in the younger age group (YOG). It was suggested that CVLs were associated with increasing age, and the concomitant CVLs may modify the clinical manifestations in elderly AD patients. The CVLs were also more frequently seen in those with more VRFs than in those with less VRFs in our results. This may indicate a close relationship between the vascular risk factors and CVLs in the elderly AD patients. Previous clinical studies have documented a close relationship between CVLs and risk of AD. Most of those factors have been shown to be associated with subcortical small-vessel lesions detected on MRI such as lacunar infarction [16–19], WMLs [20–23], and old microbleeds [24–32]. Clinical significance of lacunar infarcts has been suggested in previous clinicopathological and epidemiological studies [1–3]. Even silent small infarcts are considered to be a risk for subsequent stroke as well as cognitive deterioration in dementia. Although the exact mechanisms concerning the role of small vessel lesions in clinical manifestation of dementia are not yet fully explained, the disconnection of the subcortical network can be a candidate for the possible cause of cognitive deterioration in elderly AD patients. The OMBs were more frequently detected in those with APOE4 in our results, and this may imply an association with underlying cerebral amyloid angiopathy (CAA). In previous reports, OMBs have
Fig. 5. MRI findings in YOG and OOG.
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Fig. 6. MRI findings in those with less than 2 VRFs and those with 2 or more VRFs.
Fig. 7. Grade of white matter lesions in YOG and OOG.
Fig. 8. Grade of white matter lesions in those with less than 2 VRFs and those with 2 or more VRFs.
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Fig. 9. Mean MMSE scores according to the grade of white matter lesions.
been associated with increasing age [24–27], lacunar infarcts and white matter lesions [24,27,28], hypertension [24–27], diabetes mellitus [26], smoking [24,27], and APOE 4 alleles [24]. Lobar or cortical OMBs are usually attributed to the CAA, whereas subcortical or basal ganglionic OMBs are generally associated with VRFs such as hypertension [29–31]. Ischemic cerebrovascular lesions are considered to enhance the severity of cognitive impairment in AD patients. Regardless of symptomatic or silent lesions, the subcortical small lesions such as thalamic and basal ganglia lacunar infarcts are considered to have greater impact on the cognitive ability in patients with AD pathology, and to accelerate the tempo of cognitive decline. Those effects of CVLs are more pronounced in patients in the early stages of AD. Therefore, the coexisting CVLs may accelerate disease progression in elderly AD patients. As the severity of CVLs was associated with increasing age and number of VRF in our results, the strict management of those VRFs is prerequisite in the prevention and treatment of elderly AD patients. Reference [1] Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA 1997;277:813–7. [2] Esiri MM, Nagy Z, Smith MZ, Barnetson L, Smith AD. Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer's disease. Lancet 1999;354:919–20. [3] Lee JH, Olichney JM, Hansen LA, Hofstetter CR, Thal LJ. Small concomitant vascular lesions do not influence rates of cognitive decline in patients with Alzheimer disease. Arch Neurol 2000;57:1474–9. [4] Zekry D, Duyckaerts C, Moulias R, Belmin J, Geoffre C, Herrmann F, et al. Degenerative and vascular lesions of the brain have synergistic effects in dementia of the elderly. Acta Neuropathol (Berl) 2002;103:481–7. [5] Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, et al. Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study. BMJ 2001;322:1447–51. [6] Hofman A, Ott A, Breteler MM, Bots ML, Slooter AJ, van Harskamp F, et al. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study. Lancet 1997;349:151–4. [7] Skoog I, Lernfelt B, Landahl S, Palmertz B, Andreasson LA, Nilsson L, et al. 15-year longitudinal study of blood pressure and dementia. Lancet 1996;347:1141–5. [8] Chui HC, Zarow C, Mack WJ, Ellis WG, Zheng L, Jagust WJ, et al. Cognitive impact of subcortical vascular and Alzheimer's disease pathology. Ann Neurol 2006;60:677–87. [9] Biessels GJ, Deary IJ, Ryan CM. Cognition and diabetes: a lifespan perspective. Lancet Neurol 2008;7:184–90. [10] Hanyu H, Nakano S, Abe S, Arai H, Iwamoto T, Takasaki M. Differential diagnosis of Alzheimer-type dementia and vascular dementia based on neuroimaging study. No To Shinkei 1995;47:665–70.
91
[11] Hanyu H, Nakano S, Abe S, Arai H, Iwamoto T, Takasaki M. Differences of neuroimaging between early-onset and late-onset Alzheimer-type dementia. Rinsho Shinkeigaku 1995;35:1104–9. [12] McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34:939–44. [13] Fazekas F, Niederkorn K, Schmidt R, Offenbacher H, Horner S, Bertha G, et al. White matter signal abnormalities in normal individuals: correlation with carotid ultrasonography, cerebral blood flow measurements, and cerebrovascular risk factors. Stroke 1988;19:1285–8. [14] van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol 2010;9:167–76. [15] Yates PA, Sirisriro R, Villemagne VL, Farquharson S, Masters CL, Rowe CC. AIBL Research Group: cerebral microhemorrhage and brain β-amyloid in aging and Alzheimer disease. Neurology 2011;77:48–54. [16] Bernick C, Kuller L, Dulberg C, Longstreth Jr WT, Manolio T, Beauchamp N, et al. Cardiovascular Health Study Collaborative Reseach Group: silent MRI infarcts and the risk of future stroke: the cardiovascular health study. Neurology 2001;57:1222–9. [17] Gold G, Kövari E, Herrmann FR, Canuto A, Hof PR, Michel JP, et al. Cognitive consequences of thalamic, basal ganglia, and deep white matter lacunes in brain aging and dementia. Stroke 2005;36:1184–8. [18] Benisty S, Gouw AA, Porcher R, Madureira S, Hernandez K, Poggesi A, et al. Location of lacunar infarcts correlates with cognition in a sample of non-disabled subjects with age-related white-matter changes: the LADIS study. J Neurol Neurosurg Psychiatry 2009;80:478–83. [19] Strozyk D, Dickson DW, Lipton RB, Katz M, Derby CA, Lee S, et al. Contribution of vascular pathology to the clinical expression of dementia. Neurobiol Aging 2010;31:1710–20. [20] Liao D, Cooper L, Cai J, Toole J, Bryan N, Burke G, et al. The prevalence and severity of white matter lesions, their relationship with age, ethnicity, gender, and cardiovascular disease risk factors: The ARIC study. Neuroepidemiology 1997;16: 149–62. [21] Longstreth Jr WT, Manolio TA, Arnold A, Burke GL, Bryan N, Jungreis CA, et al. Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people: the cardiovascular health study. Stroke 1996;27:1274–82. [22] Longstreth Jr WT, Manolio TA, Arnold A, Burke GL, Bryan N, Jungreis CA, et al. Progression of cerebral white matter hyperintensities on MRI is related to diastolic blood pressure. Neurology 1998;51:319–20. [23] Carmichael O, Schwarz C, Drucker D, Fletcher E, Harvey D, Beckett L, et al. Alzheimer's Disease Neuroimaging Initiative: longitudinal changes in white matter disease and cognition in the first year of the Alzheimer disease neuroimaging initiative. Arch Neurol 2010;67:1370–8. [24] Viswanathan A, Chabriat H. Cerebral microhemorrhage. Stroke 2006;37:550–5. [25] Poels MM, Vernooij MW, Ikram MA, Hofman A, Krestin GP, van der Lugt A, et al. Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam scan study. Stroke 2010;41:S103–6. [26] Jeerakathil T, Wolf PA, Beiser A, Hald JK, Au R, Kase CS, et al. Cerebral microbleeds: prevalence and associations with cardiovascular risk factors in the Framingham Study. Stroke 2004;35:1831–5. [27] Roob G, Schmidt R, Kapeller P, Lechner A, Hartung HP, Fazekas F. MRI evidence of past cerebral microbleeds in a healthy elderly population. Neurology 1999;52: 991–4. [28] Tsushima Y, Tanizaki Y, Aoki J, Endo K. MR detection of microhemorrhages in neurologically healthy adults. Neuroradiology 2002;44:31–6. [29] Goos JD, Henneman WJ, Sluimer JD, Vrenken H, Sluimer IC, Barkhof F, et al. Incidence of cerebral microbleeds. Neurology 2010;74:1954–60. [30] Pettersen JA, Sathiyamoorthy G, Gao FQ, Szilagyi G, Nadkarni NK, St GeorgeHyslop P, et al. Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study. Arch Neurol 2008;65: 790–5. [31] Greenberg SM, Vernooij MW, Cordonnier C, Viswanathan A, Al-Shahi Salman R, Warach S, et al. Microbleed Study Group: cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 2009;8:165–74. [32] Vernooij MW, van der Lugt A, Ikram MA, Wielopolski PA, Niessen WJ, Hofman A, et al. Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurology 2008;70:1208–14.