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Cited by 172Cerebrovascular and genetic disordersNeurological Disease Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration Mechanisms

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Frontal white matter hyperintensities, clasmatodendrosis and gliovascular abnormalities in ageing and post-stroke dementia

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Chen, Aiqing, Akinyemi, Rufus O., Hase, Yoshiki, Firbank, Michael J., Ndung’u, Michael N., Foster, Vincent, Craggs, Lucy J. L., Washida, Kazuo, Okamoto, Yoko, Thomas, Alan J., Polvikoski, Tuomo M., Allan, Louise M., Oakley, Arthur E., O’Brien, John T., Horsburgh, Karen, Ihara, Masafumi, Kalaria, Raj N.·2016·Brain
DOI 10.1093/brain/awv328PMC PMC4905522
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Abstract

White matter hyperintensities as seen on brain T2-weighted magnetic resonance imaging are associated with varying degrees of cognitive dysfunction in stroke, cerebral small vessel disease and dementia. The pathophysiological mechanisms within the white matter accounting for cognitive dysfunction remain unclear. With the hypothesis that gliovascular interactions are impaired in subjects with high burdens of white matter hyperintensities, we performed clinicopathological studies in post-stroke survivors, who had exhibited greater frontal white matter hyperintensities volumes that predicted shorter time to dementia onset. Histopathological methods were used to identify substrates in the white matter that would distinguish post-stroke demented from post-stroke non-demented subjects. We focused on the reactive cell marker glial fibrillary acidic protein (GFAP) to study the incidence and location of clasmatodendrosis, a morphological attribute of irreversibly injured astrocytes. In contrast to normal appearing GFAP+ astrocytes, clasmatodendrocytes were swollen and had vacuolated cell bodies. Other markers such as aldehyde dehydrogenase 1 family, member L1 (ALDH1L1) showed cytoplasmic disintegration of the astrocytes. Total GFAP+ cells in both the frontal and temporal white matter were not greater in post-stroke demented versus post-stroke non-demented subjects. However, the percentage of clasmatodendrocytes was increased by >2-fold in subjects with post-stroke demented compared to post-stroke non-demented subjects (P = 0.026) and by 11-fold in older controls versus young controls (P < 0.023) in the frontal white matter. High ratios of clasmotodendrocytes to total astrocytes in the frontal white matter were consistent with lower Mini-Mental State Examination and the revised Cambridge Cognition Examination scores in post-stroke demented subjects. Double immunofluorescent staining showed aberrant co-localization of aquaporin 4 (AQP4) in retracted GFAP+ astrocytes with disrupted end-feet juxtaposed to microvessels. To explore whether this was associated with the disrupted gliovascular interactions or blood-brain barrier damage, we assessed the co-localization of GFAP and AQP4 immunoreactivities in post-mortem brains from adult baboons with cerebral hypoperfusive injury, induced by occlusion of three major vessels supplying blood to the brain. Analysis of the frontal white matter in perfused brains from the animals surviving 1-28 days after occlusion revealed that the highest intensity of fibrinogen immunoreactivity was at 14 days. At this survival time point, we also noted strikingly similar redistribution of AQP4 and GFAP+ astrocytes transformed into clasmatodendrocytes. Our findings suggest novel associations between irreversible astrocyte injury and disruption of gliovascular interactions at the blood-brain barrier in the frontal white matter and cognitive impairment in elderly post-stroke survivors. We propose that clasmatodendrosis is another pathological substrate, linked to white matter hyperintensities and frontal white matter changes, which may contribute to post-stroke or small vessel disease dementia.

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Graphical abstract White matter hyperintensities are associated with post-stroke cognitive dysfunction, but the underlying mechanisms are unclear. Chen et al. provide evidence from human and experimental studies that clasmatodendrosis – a marker of irreversible astrocyte damage – and gliovascular abnormalities are increased in the frontal white matter of subjects who succumb to vascular dementia.
Graphical abstract White matter hyperintensities are associated with post-stroke cognitive dysfunction, but the underlying mechanisms are unclear. Chen et al. provide evidence from human and experimental studies that clasmatodendrosis – a marker of irreversible astrocyte damage – and gliovascular abnormalities are increased in the frontal white matter of subjects who succumb to vascular dementia.CC BY-NC · PubMed Central
Figure 1 Frontal white matter hyperintensities and associated pathology in stroke survivors . ( A ) Survival curves show progression time to dementia by the presence of frontal white matter hyperintensities volume in non-demented (PSND, top ) and demented (PSD, bottom ) subjects. The mean number of days from stroke to dementia in the non-demented and DSM IV demented groups was 1483 ± 922 and 1059 ± 676 ( P = 0.001). ( B ) MRI ( a and e ) in life and coronal sections ( b–d and f–h ) demonstrate the extent of differential white matter changes in subjects with PSND ( b–d ) and PSD ( f–h ) from the cohort described in A . [ B ( a and e )] Typical white matter hyperintensity volume differences on MRI with FLAIR in PSND ( a ) and PSD ( e ) subjects. Examples are from females aged 86 and 90 years. [ B ( b , c , f and g )] Coronal sections from the magnetic resonance scanned cases stained with Luxol fast blue and haematoxylin and eosin. Diffuse myelin changes are more evident in the PSD coronal sections. [ B ( d and h )] Adjacent sections from the same cases stained for fibrinogen immunoreactivity. [ B ( h )] shows diffuse immunoreactivity and also demonstrates in astrocytes blood–brain barrier leakage of proteins. The location of coronal sections in B ( b , c , f and g ) are shown by the white line in the axial MR scans in B(a and e ). Images in B ( d and h ) are from the frontal white matter areas represented by boxes in the haematoxylin and eosin-stained sections B ( c and g ). Scale bar = 10 µm. WMH = white matter hyperintensities.
Figure 1 Frontal white matter hyperintensities and associated pathology in stroke survivors . ( A ) Survival curves show progression time to dementia by the presence of frontal white matter hyperintensities volume in non-demented (PSND, top ) and demented (PSD, bottom ) subjects. The mean number of days from stroke to dementia in the non-demented and DSM IV demented groups was 1483 ± 922 and 1059 ± 676 ( P = 0.001). ( B ) MRI ( a and e ) in life and coronal sections ( b–d and f–h ) demonstrate the extent of differential white matter changes in subjects with PSND ( b–d ) and PSD ( f–h ) from the cohort described in A . [ B ( a and e )] Typical white matter hyperintensity volume differences on MRI with FLAIR in PSND ( a ) and PSD ( e ) subjects. Examples are from females aged 86 and 90 years. [ B ( b , c , f and g )] Coronal sections from the magnetic resonance scanned cases stained with Luxol fast blue and haematoxylin and eosin. Diffuse myelin changes are more evident in the PSD coronal sections. [ B ( d and h )] Adjacent sections from the same cases stained for fibrinogen immunoreactivity. [ B ( h )] shows diffuse immunoreactivity and also demonstrates in astrocytes blood–brain barrier leakage of proteins. The location of coronal sections in B ( b , c , f and g ) are shown by the white line in the axial MR scans in B(a and e ). Images in B ( d and h ) are from the frontal white matter areas represented by boxes in the haematoxylin and eosin-stained sections B ( c and g ). Scale bar = 10 µm. WMH = white matter hyperintensities.CC BY-NC · PubMed Central
Figure 2 Distribution of GFAP+ clasmatodendrocytes in the deep white matter regions of post-stroke survivors. ( A–C ) Panels show normal appearance of GFAP+ astrocytes in the immediate superficial layers of the white matter ( A ), retracted astrocytes at mid-level ( B ) and clasmatodendrocytes in the deep white matter, with a particularly high concentration at the level of the anterior horn of the lateral ventricles ( C ). Insets in A and C show a higher magnification of the different forms of GFAP+ astrocytes predominant in A and C , respectively. In C inset, cell vacuolation is evident. Boxes 1–3 in D delineate location of images ( A–C ), demonstrating the distribution of GFAP+ cells from the immediate subcortical layer to the deep white matter. Illustrative coronal sections ( E–H ) shows the distribution of clasmatodendrocyte densities (brown dots) in the white matter regions at different coronal levels incorporating the frontal, temporal and parietal lobes. Box in F represents approximate location of image D. Scale bars = 100 μm ( A–C ); 20 μm (insets). WM = white matter.
Figure 2 Distribution of GFAP+ clasmatodendrocytes in the deep white matter regions of post-stroke survivors. ( A–C ) Panels show normal appearance of GFAP+ astrocytes in the immediate superficial layers of the white matter ( A ), retracted astrocytes at mid-level ( B ) and clasmatodendrocytes in the deep white matter, with a particularly high concentration at the level of the anterior horn of the lateral ventricles ( C ). Insets in A and C show a higher magnification of the different forms of GFAP+ astrocytes predominant in A and C , respectively. In C inset, cell vacuolation is evident. Boxes 1–3 in D delineate location of images ( A–C ), demonstrating the distribution of GFAP+ cells from the immediate subcortical layer to the deep white matter. Illustrative coronal sections ( E–H ) shows the distribution of clasmatodendrocyte densities (brown dots) in the white matter regions at different coronal levels incorporating the frontal, temporal and parietal lobes. Box in F represents approximate location of image D. Scale bars = 100 μm ( A–C ); 20 μm (insets). WM = white matter.CC BY-NC · PubMed Central
Figure 3 Quantification of GFAP+ cell numbers in the frontal and temporal white matter in controls, PSND and PSD subjects. ( A ) Box plots show total GFAP+ astrocytes in the frontal and temporal white matter. ( B ) Box plots show ratios of the number of clasmatodendrocytes to total cells in the two white matter regions. The y -axis values are ×100. Number of samples for each group are given in Table 2 . The analysis was performed in duplicate and gave similar results. *Significance: frontal white matter total GFAP, young Control versus Control P = 0.04; temporal white matter total GFAP, young Control versus Control P = 0.007, Control versus PSND P = 0.007, Control versus PSND P = 0.018; frontal white matter ratios GFAP, young Control versus Control P = 0.023, Control versus PSD P = 0.033, PSND versus PSD P = 0.03. (Mann-Whitney U-test) between the groups. Ycontrol = young controls. Control represents age-matched subjects to all groups except young controls. WM = white matter.
Figure 3 Quantification of GFAP+ cell numbers in the frontal and temporal white matter in controls, PSND and PSD subjects. ( A ) Box plots show total GFAP+ astrocytes in the frontal and temporal white matter. ( B ) Box plots show ratios of the number of clasmatodendrocytes to total cells in the two white matter regions. The y -axis values are ×100. Number of samples for each group are given in Table 2 . The analysis was performed in duplicate and gave similar results. *Significance: frontal white matter total GFAP, young Control versus Control P = 0.04; temporal white matter total GFAP, young Control versus Control P = 0.007, Control versus PSND P = 0.007, Control versus PSND P = 0.018; frontal white matter ratios GFAP, young Control versus Control P = 0.023, Control versus PSD P = 0.033, PSND versus PSD P = 0.03. (Mann-Whitney U-test) between the groups. Ycontrol = young controls. Control represents age-matched subjects to all groups except young controls. WM = white matter.CC BY-NC · PubMed Central
Figure 4 Transformation of GFAP+ cells in the deep white matter in relation to microvessels. ( A ) Triple immunofluorescent staining of GFAP (Cy5, Dylight 650 shown in green), AQP4 (Texas Red, shown in red) and DAPI for astrocytes and their processes. A(a1–4) is from a PSND case; A ( b1–4 ) is from a PSD case. A ( c ) AQP4 staining is mainly in the end-feet of astrocytes, frequently outlining a vessel (V). A ( d ) shows an astrocyte with intermediate level of pathology: AQP4 immunostaining is also seen along the process and in the cellular membrane (white arrow). A ( d ) Area outlined in a4. A ( e ) Higher magnification of area outlined in b4 , demonstrates AQP4 is aggregated in dense peripheral cellular deposits, at the periphery of the GFAP stained swollen astrocyte. A ( f ) Another example of astrocytes with GFAP stained swollen bodies and fragmented processes, and demonstrates that AQP4 is located at the edge of cell bodies of retracted astrocytes (white arrows). A ( d–f ) The progressive degenerative change or transition of the astrocytes. DAPI was used for nuclear counterstaining, which is eventually lost from the astrocytes. ( B ) GFAP and ALDH1L1 immunoreactivities in clasmatodendrocytes in the deep white matter in a PSD subject. B ( a–d ) Clasmatodendrocytes representing degenerating GFAP+ cells (arrows in b ) lacking cytoplasmic ALDH1L1 reactivity. Scale bars in A (both in b4 and f ) = 20 µm and in B = 25 µm.
Figure 4 Transformation of GFAP+ cells in the deep white matter in relation to microvessels. ( A ) Triple immunofluorescent staining of GFAP (Cy5, Dylight 650 shown in green), AQP4 (Texas Red, shown in red) and DAPI for astrocytes and their processes. A(a1–4) is from a PSND case; A ( b1–4 ) is from a PSD case. A ( c ) AQP4 staining is mainly in the end-feet of astrocytes, frequently outlining a vessel (V). A ( d ) shows an astrocyte with intermediate level of pathology: AQP4 immunostaining is also seen along the process and in the cellular membrane (white arrow). A ( d ) Area outlined in a4. A ( e ) Higher magnification of area outlined in b4 , demonstrates AQP4 is aggregated in dense peripheral cellular deposits, at the periphery of the GFAP stained swollen astrocyte. A ( f ) Another example of astrocytes with GFAP stained swollen bodies and fragmented processes, and demonstrates that AQP4 is located at the edge of cell bodies of retracted astrocytes (white arrows). A ( d–f ) The progressive degenerative change or transition of the astrocytes. DAPI was used for nuclear counterstaining, which is eventually lost from the astrocytes. ( B ) GFAP and ALDH1L1 immunoreactivities in clasmatodendrocytes in the deep white matter in a PSD subject. B ( a–d ) Clasmatodendrocytes representing degenerating GFAP+ cells (arrows in b ) lacking cytoplasmic ALDH1L1 reactivity. Scale bars in A (both in b4 and f ) = 20 µm and in B = 25 µm.CC BY-NC · PubMed Central
Figure 5 Redistribution of AQP4 from COL4 labelled microvessels and capillaries in the deep white matter in PSD. ( A–C ) Panels show a AQP4 and COL4 labelled capillary in deep white matter of a PSND case demonstrating localization of AQP4 immunoreactivity in the vessel wall ( C ). ( D–F and insets) show lack of co-localization of AQP4 and COL4 in regions where clasmatodendrocytes were found. The disrupted distribution of AQP4 is evident in F (arrow). Scale bar = 25 µm.
Figure 5 Redistribution of AQP4 from COL4 labelled microvessels and capillaries in the deep white matter in PSD. ( A–C ) Panels show a AQP4 and COL4 labelled capillary in deep white matter of a PSND case demonstrating localization of AQP4 immunoreactivity in the vessel wall ( C ). ( D–F and insets) show lack of co-localization of AQP4 and COL4 in regions where clasmatodendrocytes were found. The disrupted distribution of AQP4 is evident in F (arrow). Scale bar = 25 µm.CC BY-NC · PubMed Central
Figure 6 Integrity of the blood–brain barrier and presence of clasmatodendrocytes in the frontal white matter in a non-human primate model of cerebral hypoperfusion. [ A ( a )] Quantification of fibrinogen reactivity in the frontal white matter of adult baboons subjected to three-vessel occlusion (3VO). Brain images [ A ( b and c )] within the graph show the approximate coronal level of sampling for immunofluorescent staining. Each time point denotes the mean level of fibrinogen from n = 4–7 animals and these results were obtained from both hemispheres. There were no differences between the right and left hemispheres. ANOVA showed that there was a high variation in fibrinogen immunoreactivity across all time points ( P < 0.01). *Significance P < 0.05 compared to 1 day and sham groups. [ B ( a–c )] Astrocytes from the frontal white matter of a sham animal, demonstrating normal distribution of GFAP [ B ( a )] and AQP4 [ B ( b )], with no sign of abnormalities. B ( c ) is the merged image of B ( a and b ). Arrows denote AQP4 around periphery of blood vessel (V). [ B(d–f )] Astrocytes in white matter of an animal after 14 days of three-vessel occlusion, demonstrating clasmatodendrosis of the astrocytes immunolabelled with GFAP [ B ( d )] and an abnormal distribution of AQP4 [ B ( e )]. B ( f ) A merged image of B ( d and e ). The inset shows high magnification of a clasmatodendrocyte identified in B ( f ) (arrow) with typical peripheral distribution of AQP4 on the cell body. Scale bar = 50 µm; inset ( f ) = 20 µm.
Figure 6 Integrity of the blood–brain barrier and presence of clasmatodendrocytes in the frontal white matter in a non-human primate model of cerebral hypoperfusion. [ A ( a )] Quantification of fibrinogen reactivity in the frontal white matter of adult baboons subjected to three-vessel occlusion (3VO). Brain images [ A ( b and c )] within the graph show the approximate coronal level of sampling for immunofluorescent staining. Each time point denotes the mean level of fibrinogen from n = 4–7 animals and these results were obtained from both hemispheres. There were no differences between the right and left hemispheres. ANOVA showed that there was a high variation in fibrinogen immunoreactivity across all time points ( P < 0.01). *Significance P < 0.05 compared to 1 day and sham groups. [ B ( a–c )] Astrocytes from the frontal white matter of a sham animal, demonstrating normal distribution of GFAP [ B ( a )] and AQP4 [ B ( b )], with no sign of abnormalities. B ( c ) is the merged image of B ( a and b ). Arrows denote AQP4 around periphery of blood vessel (V). [ B(d–f )] Astrocytes in white matter of an animal after 14 days of three-vessel occlusion, demonstrating clasmatodendrosis of the astrocytes immunolabelled with GFAP [ B ( d )] and an abnormal distribution of AQP4 [ B ( e )]. B ( f ) A merged image of B ( d and e ). The inset shows high magnification of a clasmatodendrocyte identified in B ( f ) (arrow) with typical peripheral distribution of AQP4 on the cell body. Scale bar = 50 µm; inset ( f ) = 20 µm.CC BY-NC · PubMed Central

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Authors
Chen, A., Akinyemi, R. O., Hase, Y., Firbank, M. J., Ndung’u, M. N., Foster, V., Craggs, L. J. L., Washida, K., Okamoto, Y., Thomas, A. J., Polvikoski, T. M., Allan, L. M., Oakley, A. E., O’Brien, J. T., Horsburgh, K., Ihara, M., & Kalaria, R. N.
Affiliations
  • Newcastle University (GB)
  • University of Edinburgh (GB)
  • National Cerebral and Cardiovascular Center (JP)
Corresponding author
Kalaria, Raj N.
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2015-12-14
Volume
139
Issue
1
Pages
242-258
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awv328
PMC
PMC4905522
OpenAlex
W2227183631
Cited by
172
References
56
Citations by year
2026: 15 · 2025: 12 · 2024: 10 · 2023: 10 · 2022: 30 · 2021: 19 · 2020: 18 · 2019: 16 · 2018: 16 · 2017: 14 · 2016: 10 · 2015: 1
FWCI
9.63
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Brain (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • HighWire Press Open Archive (submittedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
  • Newcastle University ePrints (Newcastle Univesity) (cc-by)
Funders
  • Alzheimer's Society
  • Dunhill Medical Trust (R277/0213)
  • Great Britain Sasakawa Foundation
  • Newcastle University
  • International Brain Research Organization
  • Newcastle upon Tyne Hospitals NHS Foundation Trust
  • SENSHIN Medical Research Foundation
  • Medical Research Council (G0400074, MR/K026992/1, G0500247, MR/L016451/1)
  • Engineering and Physical Sciences Research Council
  • Biotechnology and Biological Sciences Research Council
  • Economic and Social Research Council
  • Japan Society for the Promotion of Science (15H04271)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Cerebrovascular and genetic disorders
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
white matter hyperintensities, post-stroke dementia, astrocytes, glial fibrillary acidic protein, aquaporin-4, blood-brain barrier, cerebral small vessel disease, aging, cerebral hypoperfusion, baboon model, cognitive impairment
MeSH terms
Formyltetrahydrofolate Dehydrogenase, Aged, Aged, 80 and over, Aging, Aldehyde Dehydrogenase, Oxidoreductases Acting on CH-NH Group Donors, Animals, Astrocytes, Blood-Brain Barrier, Cognition Disorders, Dementia, Female, Frontal Lobe, Glial Fibrillary Acidic Protein, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neuropsychological Tests, Case-Control Studies, Stroke, Papio anubis, Aquaporin 4, Neuroimaging, White Matter

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