Neuropathologic correlates of white matter hyperintensities

Young, V.; Halliday, Glenda M.; Kril, Jillian J.

doi:10.1212/01.wnl.0000319691.50117.54

Cited by 305 publications

(322 citation statements)

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“…We were particularly interested in the health variables as a large body of evidence suggests that WMH have a vascular aetiology (e.g., Jeerakathil et al, 2004;Wen & Sachdev, 2004;Young, Halliday, & Kril, 2008). Our findings suggest that the WMH-RT associations found here were related to ageing rather than other physical health comorbidities in the present sample.…”

Section: Discussionmentioning

confidence: 72%

“…Although there is a broad literature relating increased IIV to neurobiological disturbance, the present results suggest that the association between RT measures and WMH is likely to be related to normal age associated deterioration rather than neuropathological decline relating to dementia up to six years following assessment. It is also important to note that the relationship between the RT metrics and WMH was not influenced RT variability and WMH in old age 15 when statistically adjusting for health measures including neurological conditions, depression, cardio-or cerebrovascular disease, cardiovascular risk factors, or APOE e4 status.We were particularly interested in the health variables as a large body of evidence suggests that WMH have a vascular aetiology (e.g., Jeerakathil et al, 2004;Wen & Sachdev, 2004;Young, Halliday, & Kril, 2008). Our findings suggest that the WMH-RT associations found here were related to ageing rather than other physical health comorbidities in the present sample.…”

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confidence: 72%

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Associations between reaction time measures and white matter hyperintensities in very old age

et al. 2017

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In old age, a relationship has been reported between intraindividual variability (IIV) in reaction time and white matter integrity as evidenced by white matter hyperintensities (WMH). However, it is unclear how far such associations are due to incipient neurodegenerative pathology in the samples investigated. The present study examined the relationship between IIV and WMH in older individuals (N=526) drawn from the Sydney Memory and Ageing Study. Using a complex reaction time (RT) task, greater IIV and mean-RT were related to a higher WMH burden in the frontal lobe. Critically, significant associations remained having taken future dementia into account suggesting that they were not explained by incipient dementia. Additionally, independent measures of executive function accounted for the association between RT metrics and WHM. The results are consistent with the view that frontally-supported cognitive processes are involved in IIV-WMH relations, and that RT measures are sensitive to compromise in white matter structures in non-demented older individuals.Key words, white matter hyperintensities, reaction time, intraindividual variability, executive function, cognition.RT variability and WMH in old age 3 IntroductionIntraindividual variability (IIV), or inconsistency (e.g., Hultsch, MacDonald, & Dixon, 2002), refers to within-person variation in cognitive performance over time, and is often measured by the trial-by-trial variation in reaction times (RT) for a given cognitive task. It is well established that ageing is accompanied by cognitive decline and slowing of processing speed (e.g., Salthouse, 2010). However, an accumulating body of research suggests older adults are also more variable than younger adults (e.g., Bielak, Cherbuin, Bunce, & Anstey, 2014), even when response speed is taken into account (Dykiert, Der, Starr, & Deary, 2012). One proposal holds that IIV is an early indicator of neurobiological disturbance (Hultsch, MacDonald, Hunter, Levy-Bencheton, & Strauss, 2000;Hultsch, Strauss, Hunter, & MacDonald, 2008). In support of this, greater variability is evident in individuals with agerelated disorders such as mild cognitive impairment and dementia (Christensen et al., 2005;Duchek et al., 2009;Gorus, De Raedt, Lambert, Lemper, & Mets, 2008;Hultsch et al., 2000;Strauss, Bielak, Bunce, Hunter, & Hultsch, 2007), Parkinson's disease (de Frias, Dixon, Fisher, & Camicioli, 2007) and also frontal lobe lesions (Stuss, Murphy, Binns, & Alexander, 2003).Given the suggestion that IIV is an indicator of neurobiological disturbance, a number of magnetic resonance imaging (MRI) studies have investigated the link between variability and structural brain measures. In healthy ageing, associations have been shown between IIV and white matter hyperintensities (WMH: Bunce et al., 2010;Bunce et al., 2007), white matter volume (Jackson, Balota, Duchek, & Head, 2012;Lovden et al., 2013;Ullen, Forsman, Blom, Karabanov, & Madison, 2008;Walhovd & Fjell, 2007) and diffusion tensor imaging metrics (e.g., FA -fractional...

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Section: Discussionmentioning

confidence: 72%

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confidence: 72%

Associations between reaction time measures and white matter hyperintensities in very old age

et al. 2017

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“…Childhood intelligence is the strongest predictor of late-life intelligence and accounts for about 40% of the variance in intelligence at age 78 . Magnetic resonance imaging (MRI)-detected white matter hyperintensities (WMH) (Young et al 2008) are associated with vascular risk factors (Murray et al 2005) and with reduced cognitive ability and dementia in older adults (Leaper et al 2001;Firbank et al 2007). We previously found that WMH contribute 14% of the variance in cognitive ability at age 78, that WMH are linked to hypertension , and it is now widely accepted that WMH are an imaging biomarker of vascular disease (Kearney-Schwartz et al 2009, Raz et al 2007, Fischer et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Brain lesions, hypertension and cognitive ageing in the 1921 and 1936 Aberdeen birth cohorts

Murray

Staff

McNeil

et al. 2011

AGE

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The objectives of this study are to model the relative effects of positive (childhood intelligence) and negative (magnetic resonance imaging (MRI)-derived white matter hyperintensities (WMH)) predictors of late-life intelligence in two well-characterised normal cohorts aged 68 and 78 and to measure the influence of hypertension on WMH and lifelong cognitive change. The Scottish Mental Surveys of 1932 and 1947 tested the intelligence of almost all school children at age 11. One hundred and one participants born in 1921 and 233 participants born in 1936 had brain MRI, with measurement of WMH using Scheltens' scale, and tests of late-life fluid intelligence. Structural equation models of the effect of childhood intelligence and brain WMH on the general intelligence factor 'g' in late life in the two samples were constructed using AMOS 18. Similar models were constructed to test the effect of hypertension on WMH and lifelong cognitive change. Fluid intelligence scores were lower and WMH scores were higher in the older samples. Hypertensive participants in both samples had more WMH than normotensive participants. The positive influence of childhood intelligence on 'g' was greater in the younger sample. The negative effect of WMH on 'g' was linear and greater in the older sample due to greater WMH burden. The negative effect of hypertension on lifelong cognitive ageing was all mediated via MRIderived brain WMH. The positive relationship between AGE (2012)

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“…Ischemic stroke that occurs in the white matter often results in degeneration of OLs and demyelination (5,6). Consequently, patients with white matter stroke suffer from a wide range of neurological dysfunctions.…”

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confidence: 99%

High-mobility group box-1 as an autocrine trophic factor in white matter stroke

Choi

Cui

Chowdhury

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Maintenance of white matter integrity in health and disease is critical for a variety of neural functions. Ischemic stroke in the white matter frequently results in degeneration of oligodendrocytes (OLs) and myelin. Previously, we found that toll-like receptor 2 (TLR2) expressed in OLs provides cell-autonomous protective effects on ischemic OL death and demyelination in white matter stroke. Here, we identified high-mobility group box-1 (HMGB1) as an endogenous TLR2 ligand that promotes survival of OLs under ischemic stress. HMGB1 rapidly accumulated in the culture medium of OLs exposed to oxygen-glucose deprivation (OGD). This conditioned medium exhibited a protective activity against ischemic OL death that was completely abolished by immunodepletion of HMGB1. Knockdown of HMGB1 or application of glycyrrhizin, a specific HMGB1 inhibitor, aggravated OGD-induced OL death, and recombinant HMGB1 application reduced the extent of OL death in a TLR2-dependent manner. We confirmed that cytosolic translocation of HMGB1 and activation of TLR2-mediated signaling pathways occurred in a focal white matter stroke model induced by endothelin-1 injection. Animals with glycyrrhizin coinjection showed an expansion of the demyelinating lesion in a TLR2-dependent manner, accompanied by aggravation of sensorimotor behavioral deficits. These results indicate that HMGB1/ TLR2 activates an autocrine trophic signaling pathways in OLs and myelin to maintain structural and functional integrity of the white matter under ischemic conditions. white matter stroke | oligodendrocyte | toll-like receptor 2 | HMGB1 | myelination W hite matter in the vertebrate brain is characterized by the presence of myelinated axonal fibers and glial cells, predominantly myelin-producing oligodendrocytes (OLs) (1). The myelin sheath enables rapid communication of neural signals at a millisecond timescale between different parts of the cerebral cortex or different regions of the CNS (2). Therefore, maintaining the integrity of white matter in health and disease, especially of OLs and the myelin sheath, is critical to the performance of a variety of brain functions. Furthermore, recent studies have shown that myelination and OL generation in adulthood are actively regulated in response to neural activities (3, 4), highlighting the potential contribution of white matter plasticity to learning and higher cognitive functions.Ischemic stroke that occurs in the white matter often results in degeneration of OLs and demyelination (5, 6). Consequently, patients with white matter stroke suffer from a wide range of neurological dysfunctions. For example, focal ischemic stroke in the internal capsule may result in severe hemiparesis (7). Furthermore, both cognitive deficits and gait disturbance are hallmarks of Binswanger's subcortical vascular dementia that is the most severe form of white matter stroke (8). How ischemia leads to OL degeneration and demyelination is poorly understood. We previously reported that toll-like receptor 2 (TLR2) expressed in OLs plays a protect...

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Neuropathologic correlates of white matter hyperintensities

Abstract: White matter hyperintensities (WMH) involve a loss of vascular integrity, confirming the vascular origin of these lesions. This damage to the vasculature may in turn impair blood-brain barrier integrity and be one mechanism by which WMH evolve.

Cited by 305 publications

References 28 publications

Associations between reaction time measures and white matter hyperintensities in very old age

Associations between reaction time measures and white matter hyperintensities in very old age

Brain lesions, hypertension and cognitive ageing in the 1921 and 1936 Aberdeen birth cohorts

High-mobility group box-1 as an autocrine trophic factor in white matter stroke

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