Original Paper Received: April 28, 2013 Accepted: August 12, 2013 Published online: November 23, 2013
Cerebrovasc Dis 2013;36:412–417 DOI: 10.1159/000355042
Superficial Siderosis of the Central Nervous System: A Post-Mortem 7.0-Tesla Magnetic Resonance Imaging Study with Neuropathological Correlates J. De Reuck a V. Deramecourt a, b, c, h C. Cordonnier a, d F. Auger a, e N. Durieux a, e F. Pasquier a, b R. Bordet a, f L. Defebvre a, g D. Caparros-Lefebvre i C.A. Maurage a, c, h D. Leys a, d
Université Lille Nord de France, UDSL, EA 1046, b Memory Clinic, c Department of Pathology, d Stroke Department, Imaging Platform, Research Pole, f Department of Pharmacology and g Movement Disorder Department, Lille University Hospital, h INSERM U837, Lille, and i Centre Hospitalier, Wattrelos, France
e
Key Words Post-mortem brains · Superficial siderosis · 7.0-tesla magnetic resonance imaging · Cerebral amyloid angiopathy · Neurodegenerative diseases · Intracerebral haemorrhage · Cortical microbleed · Cortical micro-infarct
Abstract Background: Superficial siderosis (SS) is a rare finding on T2*-weighted magnetic resonance imaging (MRI), regarded as a radiological marker of cerebral amyloid angiopathy (CAA). The present study investigates with 7.0-tesla MRI the prevalence of SS and its underlying pathological substrate in a consecutive series of post-mortem brains of elderly patients with various neurodegenerative and cerebrovascular lesions. Materials and Methods: The prevalence of SS and associated lesions was screened using 7.0-tesla MRI and their neuropathological correlates in 120 post-mortem brains of patients with various neurodegenerative and cerebrovascular diseases. Results: Eighty-three separate zones of SS were detected in 45 brains (37.5%), including 25 areas of disseminated SS (dSS) and 58 areas of focal SS (fSS), restricted to less
© 2013 S. Karger AG, Basel 1015–9770/13/0366–0412$38.00/0 E-Mail [email protected] www.karger.com/ced
than 3 sulci. dSS was spatially related to sequels of 14 lobar haematomas and 11 cerebral infarcts, while fSS was connected to 19 microbleeds and 39 micro-infarcts (p < 0.001). Comparison of the 15 CAA to the 30 non-CAA brains showed that dSS was due to an old lobar haematoma in 53% of the former group compared to 3% of the latter group (p = 0.003). fSS was due to a microbleed in 7% of the CAA brains and to 40% of the non-CAA brains (p = 0.03). Conclusions: SS is associated with both haemorrhagic and ischaemic underlying lesions. It is frequently observed on T2*-weighted 7.0-tesla MRI, and two types of SS may be described. Clinicians should keep in mind that SS may be found in other settings than CAA. © 2013 S. Karger AG, Basel
Introduction
Superficial siderosis (SS) of the central nervous system is a rare condition, observed on gradient echo T2*weighted magnetic resonance imaging (MRI) as a typical signal hypo-intensity outlining the brain surface [1]. It is Jacques L. De Reuck, MD, PhD Leopold II laan 96 BE–9000 Ghent (Belgium) E-Mail dereuck.j @ gmail.com
Downloaded by: St. Andrews University 138.251.14.35 - 1/17/2014 7:19:15 PM
a
Materials and Methods Patients and Materials One hundred and twenty patients who had been followed up at the Lille University Hospital (Stroke Department, Memory Clinic or Movement Disorders Department) or Wattrelos Hospital underwent an autopsy. The brain tissue samples were obtained from the Lille Neuro-Bank of Lille University, federated to the Centre des Resources Biologiques, which acted as the institutional review board. One fresh cerebral hemisphere was deeply frozen for biochemical examination. The remaining hemisphere, the brainstem and most of the cerebellum were fixed in formalin for 3 weeks. After fixation, the cerebral leptomeninges were removed, whenever possible without harming the underlying cortex. The fixed hemisphere was sliced into coronal sections with a thickness of 1 cm. In some cases, an additional horizontal section with a thickness of 1 cm was also performed through the pons and cerebellum at the level of the dentate nucleus. MRI Examination We used a 7.0-tesla MRI (Bruker BioSpin SA) with an issuerreceiver cylinder coil with an inner diameter of 72 mm (Ettlingen, Germany). The samples were placed in a plastic box filled with physiological serum that did not allow significant tissue movements. Air bubbles as artefacts were carefully avoided. Three MRI sequences were used: a positioning sequence, a T2 sequence and a gradient echo T2* sequence. The positioning sequence allowed determination of the three-directional position of the brain section inside the magnet. The thickness of the T2weighted images was 1 mm. The field of view was a 9-cm square slide that was coded by a 256 matrix. This spin echo sequence offered the opportunity to realize T2-weighted images by using a
Post-Mortem 7.0-Tesla MRI of SS
long time of repetition and echo time. In the present study, the time of repetition and echo time were 2,500 and 33 ms, respectively. The acquisition time of this sequence was 80 s. The field of view of the gradient echo T2* (time of repetition of 60 ms and echo time of 22 ms; a flip angle of 30°; number of excitation of 10) sequence was coded by a 512 matrix. The slice thickness was 0.2 mm. The acquisition time of the sequence was 10 min. Twenty-eight brains were examined on 6 serial coronal sections of a cerebral hemisphere and on one horizontal section through the pons and cerebellum. In the 92 other brains, 3 coronal sections of a cerebral hemisphere were performed and in 65 of them a horizontal section through the brainstem and cerebellum was performed. The absence or presence and the degree of siderosis was evaluated by three observers (J.D.R., F.A. and N.D.). Zones of disseminated superficial siderosis (dSS) were predefined as affecting 3 or more sulci of the brain surface and when clearly visible on nakedeye examination. The term focal SS (fSS) was used when only detected on the coronal sections in less than 3 sulci. Neuropathological Examination For diagnostic purposes, small brain samples were taken from the primary motor cortex; the associated frontal, temporal and parietal cortex; the primary and secondary visual cortex; the cingulate gyrus; the basal nucleus of Meynert; the amygdaloid body, and the hippocampus, basal ganglia, mesencephalon, pons, medulla, cerebellum and cervical spinal cord. Slides from paraffin-embedded sections were immune-stained for protein tau, β-amyloid, α-synuclein, prion protein, TDP-43 and ubiquitin. The disease diagnosis was made according to the validated neuropathological criteria [8]. The degree of CAA was evaluated on slides from the hippocampus, the associated parietal and temporal cortex, and the visual cortex, stained for β-amyloid. CAA remained the diagnosis in 22 brains, in which a majority of β-amyloid-stained vessels were present in at least 3 of the 4 examined samples and as not-CAA, when absent or scarce, in case of a few stained vessels in 1 or 2 slides. The brain samples of the SS and their underlying lesions, detected on MRI examination, were stained with haematoxylin-eosin, luxol fast blue and Perl. Statistical Analyses Univariate comparisons of unpaired groups were done with Fisher’s exact test for categorical data. The non-parametric MannWhitney U test was used to compare continuous variables. The significance level was set at 0.05, two-tailed.
Results
Patient Characteristics Out of a series of 120 patients (median age: 70 years, interquartile range: 60–81; 56% male) with neurodegenerative and cerebrovascular diseases, 45 had areas of SS on post-mortem MRI examination of the brain. Table 1 summarizes the underlying diseases of these patients. Complete clinical data were obtained in 43 out of the 45 patients (95.5%). Thirteen brains displayed large-vessel Cerebrovasc Dis 2013;36:412–417 DOI: 10.1159/000355042
413
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due to haemosiderin deposition in the subpial space of the brain and was initially considered as the consequence of recurrent and persistent bleeding into the subarachnoid space [2, 3]. In SS, with a predilection for the cerebral convexity, cerebral amyloid angiopathy (CAA) is considered the most common cause in elderly individuals [4]. On the other hand, the classic clinical presentation of SS includes adult-onset slowly progressive gait ataxia with cerebellar dysarthria and sensorineural hearing impairment, typically affecting the brainstem and fossa posterior [1]. Some authors have even proposed including SS to the Boston diagnostic criteria for CAA [5, 6]; however, a definite diagnosis of CAA still requires a full post-mortem examination [7]. In a cohort of elderly patients with various neurodegenerative and cerebrovascular diseases, we aim to describe the prevalence of the non-classical SS in post-mortem MRI and to identify the associated neuropathological lesions. In particular, the relation between CAA and SS is investigated.
a
b
of a cerebral hemisphere at distance from an old lobar haematoma of a patient with CAA. There is an extensive leptomeningeal hypointensity signal on the T2*-weighted image representing diffuse SS
Table 1. Neuropathological diagnosis in the 45 brains with SS
CAA Alzheimer features Lewy body features Frontotemporal lobar degeneration Alzheimer dementia Vascular dementia Lewy body dementia Progressive supranuclear palsy Corticobasal degeneration Asymptomatic cerebral infarcts
15 7 1 10 9 3 3 2 1 2
Values represent n.
Table 2. Vascular risk factors and the use of antithrombotic agents in 43 out of the total population of 45 patients with SS
Arterial hypertension Hypercholesterolaemia Diabetes Smoking Antithrombotic agents
40 38 11 13 40
Numbers represent percentages.
414
Cerebrovasc Dis 2013;36:412–417 DOI: 10.1159/000355042
(arrows). Note the ‘blooming’ effect in the post-mortem thrombi of leptomeningeal vessels (white circles within the vessel). b Histological correlate of subpial haemosiderin deposits at distance from the lobar haematoma [haematoxylin-eosin stain (HE)].
atherosclerosis, and 22 displayed widespread micro-angiopathy consisting of lipohyalinosis and arteriolosclerosis. The prevalence of vascular risk factors and the use of antithrombotic agents are provided in table 2. MRI Findings Twenty-five separate zones of dSS were observed in 17 brains. Fifty-eight areas of fSS were found in 32 brains. In 4 of these brains, both areas of dSS and fSS were co-existing. Among the 25 areas of dSS, 14 were spatially related to an old lobar haematoma and 11 to an underlying cortical infarct (p = 0.64; fig. 1). Among 58 areas of fSS, 19 were spatially related to a cortical microbleed and 39 to a cortical micro-infarct (p < 0.001; fig. 2). Five brains, 1 with and 4 without CAA, displayed an area of fSS in the cerebellum due to an underlying small superficial infarct (fig. 3). All of these lesions were confirmed by the neuropathological examination. Out of the series of the 120 brains, 22 displayed significant CAA consisting of 5 territorial infarcts (23%), 9 lobar haematomas (41%), 15 cortical micro-infarcts (68%) and 5 cortical microbleeds (23%). Additionally, fifteen of them had some areas of SS. Although the prevalence of the cerebrovascular lesions between the CAA brains with and without SS was statistically not different, De Reuck et al.
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Fig. 1. a 7.0-tesla MRI T2 and T2* sequences of a coronal section
a
Fig. 2. a 7.0-tesla MRI T2 and T2* sequences of a coronal section
of a cerebral hemisphere of a patient with Lewy body dementia. A small cortical infarct (arrow) is observed on the T2 sequence, and a hypo-intensity signal at the surface of one sulcus representing fSS
b
can be seen on the T2*-weighted imaging. b The histological aspect of fSS related to a small superficial partially haemorrhagic cortical infarct [arrow; haematoxylin-eosin stain (HE)].
Fig. 3. 7.0-tesla MRI T2 and T2* sequences
there was a trend of more cerebrovascular lesions in the CAA brains (table 3). When comparing the 15 CAA brains with the 30 nonCAA brains, zones of dSS spatially related to an old cortical bleed were observed in 53 and 10%, respectively (p = 0.003), while they were related to an old infarct in 33% of the former group and 17% of the latter group (p = 0.53).
CAA brains had a higher prevalence of zones of dSS (68.2%) compared to non-CAA brains (30.6%; p = 0.01). When comparing the number of underlying lesions in areas of fSS between CAA and non-CAA brains, cortical microbleeds were found in 4 and 31%, respectively (p = 0.03), and cortical micro-infarcts were found in 32% of the former and 53% of the latter group (p = 0.25).
Post-Mortem 7.0-Tesla MRI of SS
Cerebrovasc Dis 2013;36:412–417 DOI: 10.1159/000355042
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of a horizontal section through a hemicerebellum of a patient with Alzheimer dementia. A small cortical infarct (arrow) is observed on the T2 sequence and an additional hypo-intensity signal representing fSS can be seen on the T2* imaging.
Table 3. Comparison of the prevalence of cerebrovascular lesions in CAA with and without SS
Cerebrovascular lesions CAA-SS (n = 15) CAA (n = 7) p value Territorial infarct Lobar haematoma Cortical micro-infarct Cortical microbleed
4 (27) 8 (53) 12 (80) 5 (33)
1 (14) 1 (14) 3 (43) 0 (0)
0.64 0.16 0.14 0.13
Values represent n (%).
Discussion
The present post-mortem 7.0-tesla MRI study showed that SS is more frequent than previously suspected, even in non-CAA cases. In addition to zones of dSS, areas of fSS involving only one or two cortical sulci were also detected. SS as a whole was more frequently spatially related to an underlying cortical infarct than to cortical bleed. In CAA brains, lobar haematomas were most frequently associated with zones of dSS, while areas of fSS were more frequently connected to underlying cortical micro-infarcts. They had more cerebrovascular lesions than the CAA brains without SS. A bias in the selection of the patients cannot be excluded as lobar haematomas observed clinically during life already selected patients for possible CAA at autopsy. On the other hand cortical microbleeds were not frequently observed. Nonetheless, the main finding of our study was that cortical micro-infarcts are a more frequent cause of SS than previously suspected. The number of detected small cerebral bleeds depends on the MRI characteristics, such as pulse sequence, sequence parameters, spatial resolution, magnetic field strength and image post-processing [9]. Although no comparison was performed in the present study between 7.0-tesla and 1.5- and 3.0-tesla MRI
machines, SS will probably more easily be detected with the former, as demonstrated previously for cortical microbleeds [10]. The population-based Rotterdam Scan Study, using a 1.5-tesla MRI, revealed an SS incidence of 0.7%, all of whom had cortical microbleeds in their vicinity [11]. Surprisingly, microbleeds were less frequently associated with areas of fSS than micro-infarcts. Also in a recent study, showing that SS is a warning sign for future intracranial haemorrhage, the incidence of the concomitant occurrence of SS and microbleeds was found to be low [12]. A possible explanation is that microbleeds in CAA brains are most frequently located in the deep cortical layers and do not extend up to the cortical surface [13]. On the other hand, cortical micro-infarcts more frequently extend to the cortical surface and leakage of blood develops with time, leading to some degree of haemorrhagic transformation in initially white infarcts [14]. The present study does not confirm the intriguing neuropathological observation that a solitary lobar haematoma in CAA occurs primarily in the subpial regions and extends to the cerebral cortex and underlying white matter [15]. The present study argues that SS is not exclusively observed in CAA brains. Whether its presence significantly increases the sensitivity of the Boston criteria for CAA [7] is questionable, as also demonstrated in a Dutch-type population [16]. In conclusion, we observed that SS may be associated with haemorrhagic as well as to ischaemic lesions. The intriguing relationship between SS and CAA should be studied further, but clinicians should keep in mind that SS can be found in other diseases besides CAA.
Disclosure Statement The authors report no conflicts of interest.
References
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4 Cuvincuic V, Viguier A, Calviere L, Raposo N, Larrue V, Cognard C, et al: Isolated acute nontraumatic cortical subarachnoid hemorrhage. AJNR Am J Neuroradiol 2010; 31: 1355–1362. 5 Linn J, Herms J, Dichgans M, Bruckmann H, Fesi G, Freillinger T, et al: Subarachnoid hemosiderosis and superficial cortical hemosiderosis in cerebral amyloid angiopathy. AJNR Am J Neuroradiol 2008; 29: 184– 186.
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6 Linn J, Halpin A, Demaerel P, Ruhland J, Giese AD, Dichgans M, et al: Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy. Neurology 2010;74:1346–1350. 7 Knudsen KA, Rosand J, Karluk D, Greenberg SM: Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria. Neurology 2001;56:537–539. 8 De Reuck J: The significance of small cerebral bleeds in neurodegenerative dementia syndromes. Aging Age 2012;4:307–312.
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1 Kumar N: Neuroimaging in superficial siderosis: an in-depth look. AJNR Am J Neuroradiol 2010;31:5–14. 2 Fearnley JM, Stevens JM, Rudge P: Superficial siderosis of the central nervous system. Brain 1995;118:1051–1066. 3 Koeppen AH, Michael SC, Li D, Chen Z, Cusack MJ, Gibson WM, et al: The pathology of superficial siderosis of the central nervous system. Acta Neuropathol 2008; 116: 371– 382.
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14 Hebbrecht G, Maenhout W, De Reuck J: Comparison of trace element alterations and water content in haemorrhagic and nonhaemorrhagic cerebral infarcts. Cerebrovasc Dis 1994;4:412–416. 15 Takeda S, Hinokuma K, Yamazaki K, Onda K, Miyakawa T, Ikuta F, et al: The hemorrhage caused by sporadic-type cerebral amyloid angiopathy occurs primarily in the cerebral sulci. Neuropathology 2012;32:38–43. 16 van Rooden S, van der Grond J, van den Boom R, Haan J, Linn J, Greenberg SM, et al: Descriptive analysis of the Boston criteria applied to a Dutch-type cerebral amyloid angiopathy. Stroke 2009;40:3022–3027.
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9 Greenberg SM, Vernooij MW, Cordonnier C, Viswanathan A, Al-Shari Salam R, Warach S, et al; Microbleed Study Group: cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 2009;8:165–174. 10 De Reuck J, Auger F, Cordonnier C, Deramecourt V, Durieux N, Pasquier F, et al: Comparison of 7.0-T T2*-magnetic resonance imaging of cerebral bleeds in post-mortem brain sections of Alzheimer patients with their neuropathological correlates. Cerebrovasc Dis 2011;31:511–517. 11 Vernooij MW, Ikram MA, Hofman A, Krestin GP, Breteler MM, van der Lugt A: Superficial siderosis in the general population. Neurology 2009;73:202–205.
Cerebrovasc Dis 2013;36:412–417 DOI: 10.1159/000355042
Superficial Siderosis of the Central Nervous System: A Post-Mortem 7.0-Tesla Magnetic Resonance Imaging Study with Neuropathological Correlates J. De Reuck a V. Deramecourt a, b, c, h C. Cordonnier a, d F. Auger a, e N. Durieux a, e F. Pasquier a, b R. Bordet a, f L. Defebvre a, g D. Caparros-Lefebvre i C.A. Maurage a, c, h D. Leys a, d
Université Lille Nord de France, UDSL, EA 1046, b Memory Clinic, c Department of Pathology, d Stroke Department, Imaging Platform, Research Pole, f Department of Pharmacology and g Movement Disorder Department, Lille University Hospital, h INSERM U837, Lille, and i Centre Hospitalier, Wattrelos, France
e
Key Words Post-mortem brains · Superficial siderosis · 7.0-tesla magnetic resonance imaging · Cerebral amyloid angiopathy · Neurodegenerative diseases · Intracerebral haemorrhage · Cortical microbleed · Cortical micro-infarct
Abstract Background: Superficial siderosis (SS) is a rare finding on T2*-weighted magnetic resonance imaging (MRI), regarded as a radiological marker of cerebral amyloid angiopathy (CAA). The present study investigates with 7.0-tesla MRI the prevalence of SS and its underlying pathological substrate in a consecutive series of post-mortem brains of elderly patients with various neurodegenerative and cerebrovascular lesions. Materials and Methods: The prevalence of SS and associated lesions was screened using 7.0-tesla MRI and their neuropathological correlates in 120 post-mortem brains of patients with various neurodegenerative and cerebrovascular diseases. Results: Eighty-three separate zones of SS were detected in 45 brains (37.5%), including 25 areas of disseminated SS (dSS) and 58 areas of focal SS (fSS), restricted to less
© 2013 S. Karger AG, Basel 1015–9770/13/0366–0412$38.00/0 E-Mail [email protected] www.karger.com/ced
than 3 sulci. dSS was spatially related to sequels of 14 lobar haematomas and 11 cerebral infarcts, while fSS was connected to 19 microbleeds and 39 micro-infarcts (p < 0.001). Comparison of the 15 CAA to the 30 non-CAA brains showed that dSS was due to an old lobar haematoma in 53% of the former group compared to 3% of the latter group (p = 0.003). fSS was due to a microbleed in 7% of the CAA brains and to 40% of the non-CAA brains (p = 0.03). Conclusions: SS is associated with both haemorrhagic and ischaemic underlying lesions. It is frequently observed on T2*-weighted 7.0-tesla MRI, and two types of SS may be described. Clinicians should keep in mind that SS may be found in other settings than CAA. © 2013 S. Karger AG, Basel
Introduction
Superficial siderosis (SS) of the central nervous system is a rare condition, observed on gradient echo T2*weighted magnetic resonance imaging (MRI) as a typical signal hypo-intensity outlining the brain surface [1]. It is Jacques L. De Reuck, MD, PhD Leopold II laan 96 BE–9000 Ghent (Belgium) E-Mail dereuck.j @ gmail.com
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a
Materials and Methods Patients and Materials One hundred and twenty patients who had been followed up at the Lille University Hospital (Stroke Department, Memory Clinic or Movement Disorders Department) or Wattrelos Hospital underwent an autopsy. The brain tissue samples were obtained from the Lille Neuro-Bank of Lille University, federated to the Centre des Resources Biologiques, which acted as the institutional review board. One fresh cerebral hemisphere was deeply frozen for biochemical examination. The remaining hemisphere, the brainstem and most of the cerebellum were fixed in formalin for 3 weeks. After fixation, the cerebral leptomeninges were removed, whenever possible without harming the underlying cortex. The fixed hemisphere was sliced into coronal sections with a thickness of 1 cm. In some cases, an additional horizontal section with a thickness of 1 cm was also performed through the pons and cerebellum at the level of the dentate nucleus. MRI Examination We used a 7.0-tesla MRI (Bruker BioSpin SA) with an issuerreceiver cylinder coil with an inner diameter of 72 mm (Ettlingen, Germany). The samples were placed in a plastic box filled with physiological serum that did not allow significant tissue movements. Air bubbles as artefacts were carefully avoided. Three MRI sequences were used: a positioning sequence, a T2 sequence and a gradient echo T2* sequence. The positioning sequence allowed determination of the three-directional position of the brain section inside the magnet. The thickness of the T2weighted images was 1 mm. The field of view was a 9-cm square slide that was coded by a 256 matrix. This spin echo sequence offered the opportunity to realize T2-weighted images by using a
Post-Mortem 7.0-Tesla MRI of SS
long time of repetition and echo time. In the present study, the time of repetition and echo time were 2,500 and 33 ms, respectively. The acquisition time of this sequence was 80 s. The field of view of the gradient echo T2* (time of repetition of 60 ms and echo time of 22 ms; a flip angle of 30°; number of excitation of 10) sequence was coded by a 512 matrix. The slice thickness was 0.2 mm. The acquisition time of the sequence was 10 min. Twenty-eight brains were examined on 6 serial coronal sections of a cerebral hemisphere and on one horizontal section through the pons and cerebellum. In the 92 other brains, 3 coronal sections of a cerebral hemisphere were performed and in 65 of them a horizontal section through the brainstem and cerebellum was performed. The absence or presence and the degree of siderosis was evaluated by three observers (J.D.R., F.A. and N.D.). Zones of disseminated superficial siderosis (dSS) were predefined as affecting 3 or more sulci of the brain surface and when clearly visible on nakedeye examination. The term focal SS (fSS) was used when only detected on the coronal sections in less than 3 sulci. Neuropathological Examination For diagnostic purposes, small brain samples were taken from the primary motor cortex; the associated frontal, temporal and parietal cortex; the primary and secondary visual cortex; the cingulate gyrus; the basal nucleus of Meynert; the amygdaloid body, and the hippocampus, basal ganglia, mesencephalon, pons, medulla, cerebellum and cervical spinal cord. Slides from paraffin-embedded sections were immune-stained for protein tau, β-amyloid, α-synuclein, prion protein, TDP-43 and ubiquitin. The disease diagnosis was made according to the validated neuropathological criteria [8]. The degree of CAA was evaluated on slides from the hippocampus, the associated parietal and temporal cortex, and the visual cortex, stained for β-amyloid. CAA remained the diagnosis in 22 brains, in which a majority of β-amyloid-stained vessels were present in at least 3 of the 4 examined samples and as not-CAA, when absent or scarce, in case of a few stained vessels in 1 or 2 slides. The brain samples of the SS and their underlying lesions, detected on MRI examination, were stained with haematoxylin-eosin, luxol fast blue and Perl. Statistical Analyses Univariate comparisons of unpaired groups were done with Fisher’s exact test for categorical data. The non-parametric MannWhitney U test was used to compare continuous variables. The significance level was set at 0.05, two-tailed.
Results
Patient Characteristics Out of a series of 120 patients (median age: 70 years, interquartile range: 60–81; 56% male) with neurodegenerative and cerebrovascular diseases, 45 had areas of SS on post-mortem MRI examination of the brain. Table 1 summarizes the underlying diseases of these patients. Complete clinical data were obtained in 43 out of the 45 patients (95.5%). Thirteen brains displayed large-vessel Cerebrovasc Dis 2013;36:412–417 DOI: 10.1159/000355042
413
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due to haemosiderin deposition in the subpial space of the brain and was initially considered as the consequence of recurrent and persistent bleeding into the subarachnoid space [2, 3]. In SS, with a predilection for the cerebral convexity, cerebral amyloid angiopathy (CAA) is considered the most common cause in elderly individuals [4]. On the other hand, the classic clinical presentation of SS includes adult-onset slowly progressive gait ataxia with cerebellar dysarthria and sensorineural hearing impairment, typically affecting the brainstem and fossa posterior [1]. Some authors have even proposed including SS to the Boston diagnostic criteria for CAA [5, 6]; however, a definite diagnosis of CAA still requires a full post-mortem examination [7]. In a cohort of elderly patients with various neurodegenerative and cerebrovascular diseases, we aim to describe the prevalence of the non-classical SS in post-mortem MRI and to identify the associated neuropathological lesions. In particular, the relation between CAA and SS is investigated.
a
b
of a cerebral hemisphere at distance from an old lobar haematoma of a patient with CAA. There is an extensive leptomeningeal hypointensity signal on the T2*-weighted image representing diffuse SS
Table 1. Neuropathological diagnosis in the 45 brains with SS
CAA Alzheimer features Lewy body features Frontotemporal lobar degeneration Alzheimer dementia Vascular dementia Lewy body dementia Progressive supranuclear palsy Corticobasal degeneration Asymptomatic cerebral infarcts
15 7 1 10 9 3 3 2 1 2
Values represent n.
Table 2. Vascular risk factors and the use of antithrombotic agents in 43 out of the total population of 45 patients with SS
Arterial hypertension Hypercholesterolaemia Diabetes Smoking Antithrombotic agents
40 38 11 13 40
Numbers represent percentages.
414
Cerebrovasc Dis 2013;36:412–417 DOI: 10.1159/000355042
(arrows). Note the ‘blooming’ effect in the post-mortem thrombi of leptomeningeal vessels (white circles within the vessel). b Histological correlate of subpial haemosiderin deposits at distance from the lobar haematoma [haematoxylin-eosin stain (HE)].
atherosclerosis, and 22 displayed widespread micro-angiopathy consisting of lipohyalinosis and arteriolosclerosis. The prevalence of vascular risk factors and the use of antithrombotic agents are provided in table 2. MRI Findings Twenty-five separate zones of dSS were observed in 17 brains. Fifty-eight areas of fSS were found in 32 brains. In 4 of these brains, both areas of dSS and fSS were co-existing. Among the 25 areas of dSS, 14 were spatially related to an old lobar haematoma and 11 to an underlying cortical infarct (p = 0.64; fig. 1). Among 58 areas of fSS, 19 were spatially related to a cortical microbleed and 39 to a cortical micro-infarct (p < 0.001; fig. 2). Five brains, 1 with and 4 without CAA, displayed an area of fSS in the cerebellum due to an underlying small superficial infarct (fig. 3). All of these lesions were confirmed by the neuropathological examination. Out of the series of the 120 brains, 22 displayed significant CAA consisting of 5 territorial infarcts (23%), 9 lobar haematomas (41%), 15 cortical micro-infarcts (68%) and 5 cortical microbleeds (23%). Additionally, fifteen of them had some areas of SS. Although the prevalence of the cerebrovascular lesions between the CAA brains with and without SS was statistically not different, De Reuck et al.
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Fig. 1. a 7.0-tesla MRI T2 and T2* sequences of a coronal section
a
Fig. 2. a 7.0-tesla MRI T2 and T2* sequences of a coronal section
of a cerebral hemisphere of a patient with Lewy body dementia. A small cortical infarct (arrow) is observed on the T2 sequence, and a hypo-intensity signal at the surface of one sulcus representing fSS
b
can be seen on the T2*-weighted imaging. b The histological aspect of fSS related to a small superficial partially haemorrhagic cortical infarct [arrow; haematoxylin-eosin stain (HE)].
Fig. 3. 7.0-tesla MRI T2 and T2* sequences
there was a trend of more cerebrovascular lesions in the CAA brains (table 3). When comparing the 15 CAA brains with the 30 nonCAA brains, zones of dSS spatially related to an old cortical bleed were observed in 53 and 10%, respectively (p = 0.003), while they were related to an old infarct in 33% of the former group and 17% of the latter group (p = 0.53).
CAA brains had a higher prevalence of zones of dSS (68.2%) compared to non-CAA brains (30.6%; p = 0.01). When comparing the number of underlying lesions in areas of fSS between CAA and non-CAA brains, cortical microbleeds were found in 4 and 31%, respectively (p = 0.03), and cortical micro-infarcts were found in 32% of the former and 53% of the latter group (p = 0.25).
Post-Mortem 7.0-Tesla MRI of SS
Cerebrovasc Dis 2013;36:412–417 DOI: 10.1159/000355042
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of a horizontal section through a hemicerebellum of a patient with Alzheimer dementia. A small cortical infarct (arrow) is observed on the T2 sequence and an additional hypo-intensity signal representing fSS can be seen on the T2* imaging.
Table 3. Comparison of the prevalence of cerebrovascular lesions in CAA with and without SS
Cerebrovascular lesions CAA-SS (n = 15) CAA (n = 7) p value Territorial infarct Lobar haematoma Cortical micro-infarct Cortical microbleed
4 (27) 8 (53) 12 (80) 5 (33)
1 (14) 1 (14) 3 (43) 0 (0)
0.64 0.16 0.14 0.13
Values represent n (%).
Discussion
The present post-mortem 7.0-tesla MRI study showed that SS is more frequent than previously suspected, even in non-CAA cases. In addition to zones of dSS, areas of fSS involving only one or two cortical sulci were also detected. SS as a whole was more frequently spatially related to an underlying cortical infarct than to cortical bleed. In CAA brains, lobar haematomas were most frequently associated with zones of dSS, while areas of fSS were more frequently connected to underlying cortical micro-infarcts. They had more cerebrovascular lesions than the CAA brains without SS. A bias in the selection of the patients cannot be excluded as lobar haematomas observed clinically during life already selected patients for possible CAA at autopsy. On the other hand cortical microbleeds were not frequently observed. Nonetheless, the main finding of our study was that cortical micro-infarcts are a more frequent cause of SS than previously suspected. The number of detected small cerebral bleeds depends on the MRI characteristics, such as pulse sequence, sequence parameters, spatial resolution, magnetic field strength and image post-processing [9]. Although no comparison was performed in the present study between 7.0-tesla and 1.5- and 3.0-tesla MRI
machines, SS will probably more easily be detected with the former, as demonstrated previously for cortical microbleeds [10]. The population-based Rotterdam Scan Study, using a 1.5-tesla MRI, revealed an SS incidence of 0.7%, all of whom had cortical microbleeds in their vicinity [11]. Surprisingly, microbleeds were less frequently associated with areas of fSS than micro-infarcts. Also in a recent study, showing that SS is a warning sign for future intracranial haemorrhage, the incidence of the concomitant occurrence of SS and microbleeds was found to be low [12]. A possible explanation is that microbleeds in CAA brains are most frequently located in the deep cortical layers and do not extend up to the cortical surface [13]. On the other hand, cortical micro-infarcts more frequently extend to the cortical surface and leakage of blood develops with time, leading to some degree of haemorrhagic transformation in initially white infarcts [14]. The present study does not confirm the intriguing neuropathological observation that a solitary lobar haematoma in CAA occurs primarily in the subpial regions and extends to the cerebral cortex and underlying white matter [15]. The present study argues that SS is not exclusively observed in CAA brains. Whether its presence significantly increases the sensitivity of the Boston criteria for CAA [7] is questionable, as also demonstrated in a Dutch-type population [16]. In conclusion, we observed that SS may be associated with haemorrhagic as well as to ischaemic lesions. The intriguing relationship between SS and CAA should be studied further, but clinicians should keep in mind that SS can be found in other diseases besides CAA.
Disclosure Statement The authors report no conflicts of interest.
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