Brain Pathology ISSN 1015-6305
MINI-SYMPOSIUM: White matter damage in dementia
Introduction Seth Love1; Margaret M. Esiri2 1 2
Dementia Research Group, Institute of Clinical Neurosciences, Southmead Hospital, University of Bristol, Bristol, UK. Neuropathology Department and Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK.
Keywords dementia, white matter. Correspondence author: Seth Love, PhD, FRCP, FRCPath, Dementia Research Group, Institute of Clinical Neurosciences, University of Bristol, Learning & Research Level 2, Southmead Hospital, Bristol BS16 1LE, UK (E-mail: [email protected]) Received 22 October 2014 Accepted 22 October 2014 doi:10.1111/bpa.12222
The processing power of the brain depends on the immense connectivity between neurons. The anatomical substrate for much of this connectivity is the white matter. It is therefore not surprising that white matter damage is an important contributor to dementia, and sometimes the sole cause. What is perhaps surprising is that there has been so little research on the causes and mechanisms of white matter damage in dementia (Figure 1). Our aim in this mini-symposium is to focus attention on this relatively neglected aspect of dementia, through a range of reviews of current concepts and research. Wharton et al (10) review findings that have emerged from the Medical Research Council Cognitive Function and Ageing Study, a longitudinal population-based study of cognitive impairment in the elderly in England and Wales. The study includes a brain donation program, as part of which over 450 brains have been examined to date. Post-mortem assessment of the cerebral white matter by magnetic resonance imaging (MRI) and detailed histology has shown just how common white matter lesions are in the elderly, their association with astroglial abnormalities, immune activation, oxidative injury to DNA and upregulation of hypoxiarelated genes. Several of these abnormalities can be detected even in the normal-looking white matter away from white matter lesions, suggesting widespread disturbance of white matter homeostasis in many elderly people. Hainsworth et al (3) report on their analysis of endothelial activation and vascular permeability in small blood vessels in the white matter in people with arteriolosclerotic small vessel disease (SVD). Although activation of microglia is a consistent feature of the diffuse white matter parenchymal lesions associated with SVD, the authors found little or no immunohistochemical evidence of increased expression of intercellular adhesion molecule 1 or interleukin-6, both of which are usually upregulated by inflammation, and endothelial expression of the anticoagulant, thrombomodulin, was increased rather than reduced (as might have been expected
Brain Pathology 25 (2015) 33–34 © 2014 International Society of Neuropathology
Figure 1. Bar chart display of the results of PubMed searches for all papers with “dementia” as a keyword and all with both “dementia” and “white matter” as keywords. The latter represents only a very small proportion of all publications on dementia.
had the inflammatory environment had a prothrombotic effect). There was also no increase in the amount of extravasated fibrinogen. Esiri et al (2) present novel data based on post-mortem neuropathological examination of donated brains from 224 participants in another clinical cohort study, the Oxford Project to Investigate Memory and Ageing (OPTIMA). In a previous study (7), the same group found that the severity of SVD was inversely related to cognitive score before death. In the present paper, Esiri et al have focused on the relationship between cerebral amyloid angiopathy (CAA) and SVD in the white matter. They found that the relationship between CAA and subcortical tissue damage in the OPTIMA 33
White Matter Damage in Dementia
cohort was critically dependent on APOE genotype: there was a positive relationship between measures of CAA severity and white matter SVD in ε4 carriers but a significant negative relationship in ε2 carriers. The explanation is as yet unclear but these findings suggest that we still have much to learn about the mechanisms by which APOE influences the risk and progression of dementia. Weller and colleagues showed previously that CAA in the cerebral cortex interferes with perivascular “lymphatic” drainage of interstitial fluid and the associated elimination of solutes from the brain (4, 5, 8). In this mini-symposium, the authors expand on the concept of protein elimination failure angiopathy (PEFA) in relation to the white matter as well as the gray matter (9). They pointed out that perivascular drainage is impaired by age-associated changes that stiffen the walls of intracerebral blood vessels and alter their basement membranes, and that the deleterious effects of aging on the drainage of interstitial fluid are exacerbated by the deposition of proteins, including Aβ and immune complexes, or by the development of degenerative arteriopathy, as in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The consequences are likely to include not only physical effects (eg, dilatation of perivascular spaces) but also gradual alterations in the composition of the interstitial fluid, the nature and potentially toxicity of which remain to be determined. There is increasing recognition of the contribution of cognitive impairment to the morbidity of multiple sclerosis. DeLuca et al (1) consider the relative contributions of gray and white matter disease to this cognitive impairment. The authors review clinical, radiological and pathological evidence of distinct pathological processes in gray and white matter in multiple sclerosis that are likely to make additive contributions to the development of cognitive impairment, and highlight the pressing need for longitudinal studies combining standardized neuropsychometric and neuroradiological assessments with post-mortem tissue analysis to gain better understanding of the pathogenesis of this aspect of the disease. One of the constraints on progress in the neuropathological assessment of white matter damage in dementia has been a reliance on subjective histopathological approaches that potentially conflate morphological vascular abnormalities with changes that may reflect altered interstitial fluid dynamics or white matter ischemic damage, even though the latter may be of extracranial or nonstructural etiology. Love and Miners (6) review novel biochemical approaches, including the measurement of proteins
34
Love & Esiri
involved in the molecular responses to brain ischemia, myelin proteins differentially susceptible to ischemic damage and vesselassociated proteins that allow rapid measurement of microvessel density. By combining in vivo neuroimaging data with postmortem histopathology and biochemical analysis of these and other molecular markers, the authors conclude that we now have the means to gain insight into physiological and pathological processes involved in the regulation of cerebral perfusion in the human brain and to identify an expanded range of pathogenic processes that contribute to cognitive decline.
REFERENCES 1. DeLuca GC, Yates RL, Beale H, Morrow SA (2015) Cognitive impairment in multiple sclerosis: clinical, radiologic and pathologic insights. Brain Pathol 25:79–98. 2. Esiri M, Chance S, Joachim C, Warden D, Aidan S, Sloan C et al (2015) Cerebral amyloid angiopathy, subcortical white matter disease and dementia: literature review and study in OPTIMA. Brain Pathol 25:51–62. 3. Hainsworth AH, Oommen AT, Bridges LR (2015) Endothelial cells and human cerebral small vessel disease. Brain Pathol 25:44–50. 4. Hawkes CA, Hartig W, Kacza J, Schliebs R, Weller RO, Nicoll JA, Carare RO (2011) Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol 121:431–443. 5. Hawkes CA, Sullivan PM, Hands S, Weller RO, Nicoll JA, Carare RO (2012) Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele. PLoS ONE 7:e41636. 6. Love S, Miners JS (2015) White matter hypoperfusion and damage in dementia: post-mortem assessment. Brain Pathol 25:99–107. 7. Smallwood A, Oulhaj A, Joachim C, Christie S, Sloan C, Smith AD, Esiri M (2012) Cerebral subcortical small vessel disease and its relation to cognition in elderly subjects: a pathological study in the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort. Neuropathol Appl Neurobiol 38:337–343. 8. Weller RO, Subash M, Preston SD, Mazanti I, Carare RO (2008) Perivascular drainage of amyloid-β peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer’s disease. Brain Pathol 18:253–266. 9. Weller RO, Hawkes CA, Kalaria RN, Werring DJ, Carare RO (2015) White matter changes in dementia: role of impaired drainage of interstitial fluid. Brain Pathol 25:63–78. 10. Wharton SB, Simpson JE, Brayne C, Ince PG (2015) Ageassociated white matter lesions: the MRC cognitive function and ageing study perspective. Brain Pathol 25:35–43.
Brain Pathology 25 (2015) 33–34 © 2014 International Society of Neuropathology
MINI-SYMPOSIUM: White matter damage in dementia
Introduction Seth Love1; Margaret M. Esiri2 1 2
Dementia Research Group, Institute of Clinical Neurosciences, Southmead Hospital, University of Bristol, Bristol, UK. Neuropathology Department and Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK.
Keywords dementia, white matter. Correspondence author: Seth Love, PhD, FRCP, FRCPath, Dementia Research Group, Institute of Clinical Neurosciences, University of Bristol, Learning & Research Level 2, Southmead Hospital, Bristol BS16 1LE, UK (E-mail: [email protected]) Received 22 October 2014 Accepted 22 October 2014 doi:10.1111/bpa.12222
The processing power of the brain depends on the immense connectivity between neurons. The anatomical substrate for much of this connectivity is the white matter. It is therefore not surprising that white matter damage is an important contributor to dementia, and sometimes the sole cause. What is perhaps surprising is that there has been so little research on the causes and mechanisms of white matter damage in dementia (Figure 1). Our aim in this mini-symposium is to focus attention on this relatively neglected aspect of dementia, through a range of reviews of current concepts and research. Wharton et al (10) review findings that have emerged from the Medical Research Council Cognitive Function and Ageing Study, a longitudinal population-based study of cognitive impairment in the elderly in England and Wales. The study includes a brain donation program, as part of which over 450 brains have been examined to date. Post-mortem assessment of the cerebral white matter by magnetic resonance imaging (MRI) and detailed histology has shown just how common white matter lesions are in the elderly, their association with astroglial abnormalities, immune activation, oxidative injury to DNA and upregulation of hypoxiarelated genes. Several of these abnormalities can be detected even in the normal-looking white matter away from white matter lesions, suggesting widespread disturbance of white matter homeostasis in many elderly people. Hainsworth et al (3) report on their analysis of endothelial activation and vascular permeability in small blood vessels in the white matter in people with arteriolosclerotic small vessel disease (SVD). Although activation of microglia is a consistent feature of the diffuse white matter parenchymal lesions associated with SVD, the authors found little or no immunohistochemical evidence of increased expression of intercellular adhesion molecule 1 or interleukin-6, both of which are usually upregulated by inflammation, and endothelial expression of the anticoagulant, thrombomodulin, was increased rather than reduced (as might have been expected
Brain Pathology 25 (2015) 33–34 © 2014 International Society of Neuropathology
Figure 1. Bar chart display of the results of PubMed searches for all papers with “dementia” as a keyword and all with both “dementia” and “white matter” as keywords. The latter represents only a very small proportion of all publications on dementia.
had the inflammatory environment had a prothrombotic effect). There was also no increase in the amount of extravasated fibrinogen. Esiri et al (2) present novel data based on post-mortem neuropathological examination of donated brains from 224 participants in another clinical cohort study, the Oxford Project to Investigate Memory and Ageing (OPTIMA). In a previous study (7), the same group found that the severity of SVD was inversely related to cognitive score before death. In the present paper, Esiri et al have focused on the relationship between cerebral amyloid angiopathy (CAA) and SVD in the white matter. They found that the relationship between CAA and subcortical tissue damage in the OPTIMA 33
White Matter Damage in Dementia
cohort was critically dependent on APOE genotype: there was a positive relationship between measures of CAA severity and white matter SVD in ε4 carriers but a significant negative relationship in ε2 carriers. The explanation is as yet unclear but these findings suggest that we still have much to learn about the mechanisms by which APOE influences the risk and progression of dementia. Weller and colleagues showed previously that CAA in the cerebral cortex interferes with perivascular “lymphatic” drainage of interstitial fluid and the associated elimination of solutes from the brain (4, 5, 8). In this mini-symposium, the authors expand on the concept of protein elimination failure angiopathy (PEFA) in relation to the white matter as well as the gray matter (9). They pointed out that perivascular drainage is impaired by age-associated changes that stiffen the walls of intracerebral blood vessels and alter their basement membranes, and that the deleterious effects of aging on the drainage of interstitial fluid are exacerbated by the deposition of proteins, including Aβ and immune complexes, or by the development of degenerative arteriopathy, as in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The consequences are likely to include not only physical effects (eg, dilatation of perivascular spaces) but also gradual alterations in the composition of the interstitial fluid, the nature and potentially toxicity of which remain to be determined. There is increasing recognition of the contribution of cognitive impairment to the morbidity of multiple sclerosis. DeLuca et al (1) consider the relative contributions of gray and white matter disease to this cognitive impairment. The authors review clinical, radiological and pathological evidence of distinct pathological processes in gray and white matter in multiple sclerosis that are likely to make additive contributions to the development of cognitive impairment, and highlight the pressing need for longitudinal studies combining standardized neuropsychometric and neuroradiological assessments with post-mortem tissue analysis to gain better understanding of the pathogenesis of this aspect of the disease. One of the constraints on progress in the neuropathological assessment of white matter damage in dementia has been a reliance on subjective histopathological approaches that potentially conflate morphological vascular abnormalities with changes that may reflect altered interstitial fluid dynamics or white matter ischemic damage, even though the latter may be of extracranial or nonstructural etiology. Love and Miners (6) review novel biochemical approaches, including the measurement of proteins
34
Love & Esiri
involved in the molecular responses to brain ischemia, myelin proteins differentially susceptible to ischemic damage and vesselassociated proteins that allow rapid measurement of microvessel density. By combining in vivo neuroimaging data with postmortem histopathology and biochemical analysis of these and other molecular markers, the authors conclude that we now have the means to gain insight into physiological and pathological processes involved in the regulation of cerebral perfusion in the human brain and to identify an expanded range of pathogenic processes that contribute to cognitive decline.
REFERENCES 1. DeLuca GC, Yates RL, Beale H, Morrow SA (2015) Cognitive impairment in multiple sclerosis: clinical, radiologic and pathologic insights. Brain Pathol 25:79–98. 2. Esiri M, Chance S, Joachim C, Warden D, Aidan S, Sloan C et al (2015) Cerebral amyloid angiopathy, subcortical white matter disease and dementia: literature review and study in OPTIMA. Brain Pathol 25:51–62. 3. Hainsworth AH, Oommen AT, Bridges LR (2015) Endothelial cells and human cerebral small vessel disease. Brain Pathol 25:44–50. 4. Hawkes CA, Hartig W, Kacza J, Schliebs R, Weller RO, Nicoll JA, Carare RO (2011) Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol 121:431–443. 5. Hawkes CA, Sullivan PM, Hands S, Weller RO, Nicoll JA, Carare RO (2012) Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele. PLoS ONE 7:e41636. 6. Love S, Miners JS (2015) White matter hypoperfusion and damage in dementia: post-mortem assessment. Brain Pathol 25:99–107. 7. Smallwood A, Oulhaj A, Joachim C, Christie S, Sloan C, Smith AD, Esiri M (2012) Cerebral subcortical small vessel disease and its relation to cognition in elderly subjects: a pathological study in the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort. Neuropathol Appl Neurobiol 38:337–343. 8. Weller RO, Subash M, Preston SD, Mazanti I, Carare RO (2008) Perivascular drainage of amyloid-β peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer’s disease. Brain Pathol 18:253–266. 9. Weller RO, Hawkes CA, Kalaria RN, Werring DJ, Carare RO (2015) White matter changes in dementia: role of impaired drainage of interstitial fluid. Brain Pathol 25:63–78. 10. Wharton SB, Simpson JE, Brayne C, Ince PG (2015) Ageassociated white matter lesions: the MRC cognitive function and ageing study perspective. Brain Pathol 25:35–43.
Brain Pathology 25 (2015) 33–34 © 2014 International Society of Neuropathology
