Cortical tau pathology: a major player in fibre-specific white matter reductions in Alzheimer's disease?

Cortical tau pathology: a major player in fibre-specific white matter reductions in Alzheimer's... Sir, We read with great interest the article ‘Fibre-specific white matter reductions in Alzheimer’s disease and mild cognitive impairment’ recently published by Mito and colleagues (2018). Using the novel technique of fixed-based analysis (FBA) this cross-sectional study confirmed previous findings from in vivo diffusion weighted imaging (DWI)/diffusion tensor imaging (DTI) that indicate degeneration in specific fibre pathways functionally implicated in Alzheimer’s disease, as well as new data revealing axonal reduction within the posterior cingulum in patients with mild cognitive impairment (MCI). One of the main aims of the study was to determine a potential association of amyloid-β accumulation with white matter degeneration by comparing measures of white matter tract degeneration between MCI patients with a positive amyloid-β PET scan (11C-PiB), i.e. likely representing prodromal Alzheimer’s disease dementia, and those with a negative amyloid-β PET scan. Contrary to the author’s expectations, no robust statistical differences relating to degeneration of any white matter tracts and amyloid status were revealed. However, from our point of view this is not surprising as amyloid-β pathology alone does not have an impact on cognitive performance and is not the only neuropathological correlate of Alzheimer’s disease since the latter is characterized by the presence of both amyloid-β and hyperphosphorlyated tau (HPτ) pathology. Hence, we would like to highlight the possible impact of cortical HPτ pathology on white matter degeneration in the Alzheimer’s disease and MCI cohorts investigated by Mito and colleagues (2018). We recently published quantitative neuropathological studies, using human post-mortem tissue that specifically investigated the relationship between parietal white matter degeneration and HPτ pathology in an Alzheimer’s disease and normal aged non-demented cohort (McAleese et al., 2015, 2017). In these studies we reported that (in-line with the development of Alzheimer’s disease) increasing cortical HPτ pathology, and not cerebrovascular or amyloid-β pathology, was significantly associated with, and a predictor of, white matter hyperintensity scores in post-mortem MRI of parietal and temporal regions (McAleese et al., 2015). Subsequently, we found significant differences in the pathological and molecular signatures, and hence the aetiology of parietal white matter damage between Alzheimer’s disease and non-demented controls, with white matter damage in Alzheimer’s disease being associated with a degenerative loss (i.e. Wallerian degeneration) of axons and associated demyelination as a consequence of increased cortical burden of HPτ pathology. This is in contrast to white matter damage seen in non-demented individuals that primarily demonstrated demyelination only, which was associated with cerebrovascular small vessel disease (SVD) and markers of hypoxia (McAleese et al., 2017). These were the first published human neuropathological data to clearly demonstrate differences in the pathological and molecular composition and aetiology of posterior white matter damage, and corroborate data from various neuroimaging studies, inclusive of the study by Mito and colleagues, which demonstrate Alzheimer’s disease-specific white matter changes. The specific white matter tracts exhibiting degeneration identified by Mito and colleagues connect brain regions that have been shown to be functionally implicated in Alzheimer’s disease. Furthermore, these tracts are associated with cortical areas affected early in the hierarchal progression of HPτ pathology: a key example is the parahippocampal gyrus, from which fibre pathways from the posterior cingulum, arcuate fasciculus and inferior fronto-occipital fasciculus connect. As noted by Mito and colleagues, the white matter pathways affected were mostly long association fibres. It has been shown that long (and short) fibres primarily originate from pyramidal cells in layer III and V of the cortex, which constitute the neuronal population selectively affected by HPτ pathology (Pearson et al., 1985) and as indicated by DTI studies (Bosch et al., 2012; Amlien et al., 2013; Hong et al., 2016) and human post-mortem tissue (McAleese et al., 2017), Wallerian degeneration can indeed be activated in these pyramidal cell layers and leading to degeneration of the fibre tracts. This notion supports the data from the study by Mito and colleagues as the authors found selective disruption of the posterior cingulum in the amyloid-negative MCI group, which is likely to have considerable HPτ pathology burden in the hippocampus, parahippocampal gyrus, fusiform gyrus and mid/superior temporal gyrus (i.e. neurofibrillary tangle Braak stage IV) (Braak et al., 2006). This pattern of HPτ pathology can cause neuronal and axonal transport dysfunction and initiate a degenerative Wallerian-like mechanism via the activation of protease calpain (Coleman, 2005; Ma et al., 2013). Data from human post-mortem studies have shown a strong association of the density and extent of HPτ pathology with memory deficits (Riley et al., 2002) and overall ante-mortem cognitive decline in Alzheimer’s disease (Riley et al., 2002; Giannakopoulos et al., 2003; Walker et al., 2017). These findings have since been replicated using in vivo τ-PET radiotracers that confirmed a correlation between 18F-AV-1451 PET images and Braak stages (Scholl et al., 2016; Schwarz et al., 2016) and more advanced Braak stage-like PET uptake is associated with a decline in global cognitive decline and more frequent cognitive impairment (Cho et al., 2016a; Scholl et al., 2016). Furthermore, specific cognitive domain performances, such as worse episodic memory and memory decline, are associated with higher 18F-AV-1451 uptake in the medial temporal region (Scholl et al., 2016). Importantly, the accumulation of τ-PET radiotracers is more closely related to functional and structural deterioration in Alzheimer’s disease than amyloid-β PET tracers (Cho et al., 2016b). Therefore, future studies implementing τ-PET radiotracers rather than amyloid-β PET tracers may offer a better insight into the pathological aetiology of white matter degeneration in vitam. In summary, the significant white matter loss in Alzheimer’s disease and MCI reported by Mito and colleagues is likely to be associated with cortical HPτ but not with amyloid-β pathology, respectively. These findings further strengthen the argument that white matter hyperintensities on in vivo MRI images of cognitively impaired subjects should not be interpreted as a robust indicator of cerebrovascular disease (vascular dementia) but rather they suggest Alzheimer’s disease associated cortical HPτ pathology. Funding K.E.M. is funded by the Alzheimer's Society, UK (Grant number AS-JF-001). References Amlien IK, Fjell AM, Walhovd KB, Selnes P, Stenset V, Grambaite R, et al.   Mild cognitive impairment: cerebrospinal fluid tau biomarker pathologic levels and longitudinal changes in white matter integrity. Radiology  2013; 266: 295– 303. Google Scholar CrossRef Search ADS PubMed  Bosch B, Arenaza-Urquijo EM, Rami L, Sala-Llonch R, Junque C, Sole-Padulles C, et al.   Multiple DTI index analysis in normal aging, amnestic MCI and AD. Relationship with neuropsychological performance. Neurobiol Aging  2012; 33: 61– 74. Google Scholar CrossRef Search ADS PubMed  Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol  2006; 112: 389– 404. Google Scholar CrossRef Search ADS PubMed  Cho H, Choi JY, Hwang MS, Kim YJ, Lee HM, Lee HS, et al.   In vivo cortical spreading pattern of tau and amyloid in the Alzheimer disease spectrum. Ann Neurol  2016a; 80: 247– 58. Google Scholar CrossRef Search ADS   Cho H, Choi JY, Hwang MS, Lee JH, Kim YJ, Lee HM, et al.   Tau PET in Alzheimer disease and mild cognitive impairment. Neurology  2016b; 87: 375– 83. Google Scholar CrossRef Search ADS   Coleman M. Axon degeneration mechanisms: commonality amid diversity. Nat Rev Neurosci  2005; 6: 889– 98. Google Scholar CrossRef Search ADS PubMed  Giannakopoulos P, Herrmann FR, Bussiere T, Bouras C, Kovari E, Perl DP, et al.   Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer's disease. Neurology  2003; 60: 1495– 500. Google Scholar CrossRef Search ADS PubMed  Hong YJ, Kim CM, Jang EH, Hwang J, Roh JH, Lee JH. White matter changes may precede gray matter loss in elderly with subjective memory impairment. Dement Geriatr Cogn Disord  2016; 42: 227– 35. Google Scholar CrossRef Search ADS PubMed  Ma M, Ferguson TA, Schoch KM, Li J, Qian Y, Shofer FS, et al.   Calpains mediate axonal cytoskeleton disintegration during Wallerian degeneration. Neurobiol Dis  2013; 56: 34– 46. Google Scholar CrossRef Search ADS PubMed  McAleese KE, Firbank M, Dey M, Colloby SJ, Walker L, Johnson M, et al.   Cortical tau load is associated with white matter hyperintensities. Acta Neuropathol Commun  2015; 3: 60. Google Scholar CrossRef Search ADS PubMed  McAleese KE, Walker L, Graham S, Moya ELJ, Johnson M, Erskine D, et al.   Parietal white matter lesions in Alzheimer's disease are associated with cortical neurodegenerative pathology, but not with small vessel disease. Acta Neuropathol  2017; 134: 459– 73. Google Scholar CrossRef Search ADS PubMed  Mito R, Raffelt D, Dhollander T, Vaughan DN, Donald Tournier J, Salvado O, et al.   Fibre-specific white matter reductions in Alzheimer’s disease and mild cognitive impairment. Brain  2018; 141: 888– 902. Google Scholar CrossRef Search ADS   Pearson RC, Esiri MM, Hiorns RW, Wilcock GK, Powell TP. Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer disease. Proc Natl Acad Sci USA  1985; 82: 4531– 4. Google Scholar CrossRef Search ADS PubMed  Riley KP, Snowdon DA, Markesbery WR. Alzheimer's neurofibrillary pathology and the spectrum of cognitive function: findings from the Nun Study. Ann Neurol  2002; 51: 567– 77. Google Scholar CrossRef Search ADS PubMed  Scholl M, Lockhart SN, Schonhaut DR, O'Neil JP, Janabi M, Ossenkoppele R, et al.   PET Imaging of tau deposition in the aging human brain. Neuron  2016; 89: 971– 82. Google Scholar CrossRef Search ADS PubMed  Schwarz AJ, Yu P, Miller BB, Shcherbinin S, Dickson J, Navitsky M, et al.   Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages. Brain  2016; 139 ( Pt 5): 1539– 50. Google Scholar CrossRef Search ADS PubMed  Walker L, McAleese KE, Johnson M, Khundakar AA, Erskine D, Thomas AJ, et al.   Quantitative neuropathology: an update on automated methodologies and implications for large scale cohorts. J Neural Transm  2017; 124: 671– 83. Google Scholar CrossRef Search ADS PubMed  © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Brain Oxford University Press

Cortical tau pathology: a major player in fibre-specific white matter reductions in Alzheimer's disease?

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Oxford University Press
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© The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com
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0006-8950
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10.1093/brain/awy084
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Abstract

Sir, We read with great interest the article ‘Fibre-specific white matter reductions in Alzheimer’s disease and mild cognitive impairment’ recently published by Mito and colleagues (2018). Using the novel technique of fixed-based analysis (FBA) this cross-sectional study confirmed previous findings from in vivo diffusion weighted imaging (DWI)/diffusion tensor imaging (DTI) that indicate degeneration in specific fibre pathways functionally implicated in Alzheimer’s disease, as well as new data revealing axonal reduction within the posterior cingulum in patients with mild cognitive impairment (MCI). One of the main aims of the study was to determine a potential association of amyloid-β accumulation with white matter degeneration by comparing measures of white matter tract degeneration between MCI patients with a positive amyloid-β PET scan (11C-PiB), i.e. likely representing prodromal Alzheimer’s disease dementia, and those with a negative amyloid-β PET scan. Contrary to the author’s expectations, no robust statistical differences relating to degeneration of any white matter tracts and amyloid status were revealed. However, from our point of view this is not surprising as amyloid-β pathology alone does not have an impact on cognitive performance and is not the only neuropathological correlate of Alzheimer’s disease since the latter is characterized by the presence of both amyloid-β and hyperphosphorlyated tau (HPτ) pathology. Hence, we would like to highlight the possible impact of cortical HPτ pathology on white matter degeneration in the Alzheimer’s disease and MCI cohorts investigated by Mito and colleagues (2018). We recently published quantitative neuropathological studies, using human post-mortem tissue that specifically investigated the relationship between parietal white matter degeneration and HPτ pathology in an Alzheimer’s disease and normal aged non-demented cohort (McAleese et al., 2015, 2017). In these studies we reported that (in-line with the development of Alzheimer’s disease) increasing cortical HPτ pathology, and not cerebrovascular or amyloid-β pathology, was significantly associated with, and a predictor of, white matter hyperintensity scores in post-mortem MRI of parietal and temporal regions (McAleese et al., 2015). Subsequently, we found significant differences in the pathological and molecular signatures, and hence the aetiology of parietal white matter damage between Alzheimer’s disease and non-demented controls, with white matter damage in Alzheimer’s disease being associated with a degenerative loss (i.e. Wallerian degeneration) of axons and associated demyelination as a consequence of increased cortical burden of HPτ pathology. This is in contrast to white matter damage seen in non-demented individuals that primarily demonstrated demyelination only, which was associated with cerebrovascular small vessel disease (SVD) and markers of hypoxia (McAleese et al., 2017). These were the first published human neuropathological data to clearly demonstrate differences in the pathological and molecular composition and aetiology of posterior white matter damage, and corroborate data from various neuroimaging studies, inclusive of the study by Mito and colleagues, which demonstrate Alzheimer’s disease-specific white matter changes. The specific white matter tracts exhibiting degeneration identified by Mito and colleagues connect brain regions that have been shown to be functionally implicated in Alzheimer’s disease. Furthermore, these tracts are associated with cortical areas affected early in the hierarchal progression of HPτ pathology: a key example is the parahippocampal gyrus, from which fibre pathways from the posterior cingulum, arcuate fasciculus and inferior fronto-occipital fasciculus connect. As noted by Mito and colleagues, the white matter pathways affected were mostly long association fibres. It has been shown that long (and short) fibres primarily originate from pyramidal cells in layer III and V of the cortex, which constitute the neuronal population selectively affected by HPτ pathology (Pearson et al., 1985) and as indicated by DTI studies (Bosch et al., 2012; Amlien et al., 2013; Hong et al., 2016) and human post-mortem tissue (McAleese et al., 2017), Wallerian degeneration can indeed be activated in these pyramidal cell layers and leading to degeneration of the fibre tracts. This notion supports the data from the study by Mito and colleagues as the authors found selective disruption of the posterior cingulum in the amyloid-negative MCI group, which is likely to have considerable HPτ pathology burden in the hippocampus, parahippocampal gyrus, fusiform gyrus and mid/superior temporal gyrus (i.e. neurofibrillary tangle Braak stage IV) (Braak et al., 2006). This pattern of HPτ pathology can cause neuronal and axonal transport dysfunction and initiate a degenerative Wallerian-like mechanism via the activation of protease calpain (Coleman, 2005; Ma et al., 2013). Data from human post-mortem studies have shown a strong association of the density and extent of HPτ pathology with memory deficits (Riley et al., 2002) and overall ante-mortem cognitive decline in Alzheimer’s disease (Riley et al., 2002; Giannakopoulos et al., 2003; Walker et al., 2017). These findings have since been replicated using in vivo τ-PET radiotracers that confirmed a correlation between 18F-AV-1451 PET images and Braak stages (Scholl et al., 2016; Schwarz et al., 2016) and more advanced Braak stage-like PET uptake is associated with a decline in global cognitive decline and more frequent cognitive impairment (Cho et al., 2016a; Scholl et al., 2016). Furthermore, specific cognitive domain performances, such as worse episodic memory and memory decline, are associated with higher 18F-AV-1451 uptake in the medial temporal region (Scholl et al., 2016). Importantly, the accumulation of τ-PET radiotracers is more closely related to functional and structural deterioration in Alzheimer’s disease than amyloid-β PET tracers (Cho et al., 2016b). Therefore, future studies implementing τ-PET radiotracers rather than amyloid-β PET tracers may offer a better insight into the pathological aetiology of white matter degeneration in vitam. In summary, the significant white matter loss in Alzheimer’s disease and MCI reported by Mito and colleagues is likely to be associated with cortical HPτ but not with amyloid-β pathology, respectively. These findings further strengthen the argument that white matter hyperintensities on in vivo MRI images of cognitively impaired subjects should not be interpreted as a robust indicator of cerebrovascular disease (vascular dementia) but rather they suggest Alzheimer’s disease associated cortical HPτ pathology. Funding K.E.M. is funded by the Alzheimer's Society, UK (Grant number AS-JF-001). References Amlien IK, Fjell AM, Walhovd KB, Selnes P, Stenset V, Grambaite R, et al.   Mild cognitive impairment: cerebrospinal fluid tau biomarker pathologic levels and longitudinal changes in white matter integrity. Radiology  2013; 266: 295– 303. Google Scholar CrossRef Search ADS PubMed  Bosch B, Arenaza-Urquijo EM, Rami L, Sala-Llonch R, Junque C, Sole-Padulles C, et al.   Multiple DTI index analysis in normal aging, amnestic MCI and AD. Relationship with neuropsychological performance. Neurobiol Aging  2012; 33: 61– 74. Google Scholar CrossRef Search ADS PubMed  Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol  2006; 112: 389– 404. Google Scholar CrossRef Search ADS PubMed  Cho H, Choi JY, Hwang MS, Kim YJ, Lee HM, Lee HS, et al.   In vivo cortical spreading pattern of tau and amyloid in the Alzheimer disease spectrum. Ann Neurol  2016a; 80: 247– 58. Google Scholar CrossRef Search ADS   Cho H, Choi JY, Hwang MS, Lee JH, Kim YJ, Lee HM, et al.   Tau PET in Alzheimer disease and mild cognitive impairment. Neurology  2016b; 87: 375– 83. Google Scholar CrossRef Search ADS   Coleman M. Axon degeneration mechanisms: commonality amid diversity. Nat Rev Neurosci  2005; 6: 889– 98. Google Scholar CrossRef Search ADS PubMed  Giannakopoulos P, Herrmann FR, Bussiere T, Bouras C, Kovari E, Perl DP, et al.   Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer's disease. Neurology  2003; 60: 1495– 500. Google Scholar CrossRef Search ADS PubMed  Hong YJ, Kim CM, Jang EH, Hwang J, Roh JH, Lee JH. White matter changes may precede gray matter loss in elderly with subjective memory impairment. Dement Geriatr Cogn Disord  2016; 42: 227– 35. Google Scholar CrossRef Search ADS PubMed  Ma M, Ferguson TA, Schoch KM, Li J, Qian Y, Shofer FS, et al.   Calpains mediate axonal cytoskeleton disintegration during Wallerian degeneration. Neurobiol Dis  2013; 56: 34– 46. Google Scholar CrossRef Search ADS PubMed  McAleese KE, Firbank M, Dey M, Colloby SJ, Walker L, Johnson M, et al.   Cortical tau load is associated with white matter hyperintensities. Acta Neuropathol Commun  2015; 3: 60. Google Scholar CrossRef Search ADS PubMed  McAleese KE, Walker L, Graham S, Moya ELJ, Johnson M, Erskine D, et al.   Parietal white matter lesions in Alzheimer's disease are associated with cortical neurodegenerative pathology, but not with small vessel disease. Acta Neuropathol  2017; 134: 459– 73. Google Scholar CrossRef Search ADS PubMed  Mito R, Raffelt D, Dhollander T, Vaughan DN, Donald Tournier J, Salvado O, et al.   Fibre-specific white matter reductions in Alzheimer’s disease and mild cognitive impairment. Brain  2018; 141: 888– 902. Google Scholar CrossRef Search ADS   Pearson RC, Esiri MM, Hiorns RW, Wilcock GK, Powell TP. Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer disease. Proc Natl Acad Sci USA  1985; 82: 4531– 4. Google Scholar CrossRef Search ADS PubMed  Riley KP, Snowdon DA, Markesbery WR. Alzheimer's neurofibrillary pathology and the spectrum of cognitive function: findings from the Nun Study. Ann Neurol  2002; 51: 567– 77. Google Scholar CrossRef Search ADS PubMed  Scholl M, Lockhart SN, Schonhaut DR, O'Neil JP, Janabi M, Ossenkoppele R, et al.   PET Imaging of tau deposition in the aging human brain. Neuron  2016; 89: 971– 82. Google Scholar CrossRef Search ADS PubMed  Schwarz AJ, Yu P, Miller BB, Shcherbinin S, Dickson J, Navitsky M, et al.   Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages. Brain  2016; 139 ( Pt 5): 1539– 50. Google Scholar CrossRef Search ADS PubMed  Walker L, McAleese KE, Johnson M, Khundakar AA, Erskine D, Thomas AJ, et al.   Quantitative neuropathology: an update on automated methodologies and implications for large scale cohorts. J Neural Transm  2017; 124: 671– 83. Google Scholar CrossRef Search ADS PubMed  © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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BrainOxford University Press

Published: Apr 13, 2018

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