Cited by 338Cerebrovascular and genetic disordersDementia and Cognitive Impairment ResearchNeurological Disease Mechanisms and Treatments

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Presence and progression of white matter hyperintensities and cognition: A meta-analysis

Kloppenborg, Raoul P., Nederkoorn, Paul J., Geerlings, Mirjam I., van den Berg, Esther·2014·Neurology

DOI 10.1212/wnl.0000000000000505

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Abstract

OBJECTIVE: We aimed to quantify the effects of white matter hyperintensities (WMHs) on specific cognitive functions with particular attention to WMH progression and localization. METHODS: PubMed (January 1990-July 2013) and bibliographies from included articles were used. Studies that were included (1) used MRI; (2) had a population-based or case-control design with a healthy control group that could be used for analysis; (3) matched/adjusted for age, sex, and education; and (4) addressed ≥1 predefined cognitive domains with ≥1 validated neuropsychological tests. Data were independently extracted by 2 investigators. Pearson r was extracted/calculated and used as the common metric for the effect size across studies. RESULTS: Twenty-three cross-sectional and 14 longitudinal studies were included with a total of 8,685 and 7,731 participants. Presence of WMHs was significantly associated with concurrent cognitive deficits in all examined domains: general intelligence (Fisher z -0.10, 95% confidence interval [CI] -0.19 to -0.04), memory (-0.08, -0.13 to -0.06), processing speed (-0.11, -0.17 to -0.07), attention and executive functions (-0.11, -0.16 to -0.07), and perception/construction (-0.15, -0.21 to -0.07). Similar effect sizes were observed for cognitive decline over time. WMH progression was associated with greater cognitive decline, particularly for general intelligence (Fisher z -0.31, 95% CI -0.5 to -0.02) and attention and executive functions (-0.32, -0.34 to -0.28). CONCLUSIONS: The small but robust and consistent effects of WMHs on all cognitive domains suggest a more global effect on cognition than previously thought. Progression of WMHs was associated with even worse cognitive functioning, most pronounced in attention and executive functioning.

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Background
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Background
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BackgroundMethodResultInfluential
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“The progression of WMHs was associated with even worse cognitive functioning, most pronounced in attention and executive functioning (31).”
Background
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“59 The BCAS model exhibited working memory deficits due to myelin loss in the corpus callosum and other white matter regions, which is consistent with the pathological and clinical findings in human patients with WMH of vascular origin.”
Result
White matter hyperintensity load mediates the relationship between age and cognition
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“…which are evident hyperintensities (Liu et al. 2016) or bright areas on magnetic resonance imaging (MRI) (Debette andMarkus 2009; Torres et al. 2015; Vesperman et al. 2018) The presence and progression of WMH are considered an indicator of cognitive decline (Kloppenborg and Geerlings 2014).”
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“Impaired domains include memory, processing speed, attention, executive function, and perception/construction.(3) Moreover, WMH predict future cognitive decline(4) and WMH progression tracks with decline in attention and executive function.”
Background
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“Although effect sizes were slightly larger than reported in the meta-analysis [29], they were also small to modest [30].”
Influential
White matter hyperintensity volumes are related to processing speed in long-term survivors of childhood cerebellar tumors
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“Systematic reviews in both older adults and clinical populations show that larger quantified WMH volumes are associated with decreases in cognitive outcomes, with the strongest relationships seen with cognitive processing speed [3, 12].”
BackgroundMethod
Damage to white matter networks resulting from small vessel disease and the effects on cognitive function
Busby, N., Wilmskoetter, J., Newman‐Norlund, R., Newman-Norlund, S. E., Sayers, S., Wilson, S. C., Riccardi, N., Teghipco, A., Roth, R. W., Bakos, L., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-13813-7 · Cited by 7
“For example, several prior studies discuss the presence of WMHs affecting executive functions and memory 14–16 whilst others have found a more global impact on cognition 9 .”
To what extent does white matter map to cognition in bipolar disorder? A systematic review of the evidence
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Vascular Burden Moderates the Relationship Between ADHD and Cognition in Older Adults
Callahan, B. L., Becker, S., Ramirez, J., Taylor, R., Shammi, P., Gao, F., & Black, S. E. (2023) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2023.10.018 · Cited by 7
Tract Specific White Matter Lesion Load Affects White Matter Microstructure and Their Relationships With Functional Connectivity and Cognitive Decline
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Obstructive sleep apnea and white matter hyperintensities: correlation or causation?
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“…et al., 2014; Fazekas et al., 1987; Nishibayashi et al., 2008) cerebral small vessel disease due to OSA has also been implicated; (Zimmerman et al., 2006; Kloppenborg et al., 2014) however, this has not been definitive, necessitating a more detailed investigation into WMH to elucidate more…”
BackgroundInfluential
Relation of white matter hyperintensities and motor deficits in chronic stroke
Hicks, J. M., Taub, E., Womble, B., Barghi, A., Rickards, T. A., Mark, V. W., & Uswatte, G. (2018) · Restorative Neurology and Neuroscience · doi:10.3233/rnn-170746 · Cited by 7
“Many studies have associated WMHs with cognitive decline and aging (Kloppenborg, Nederkoorn, Geerlings, & van den Berg, 2014).”

Authors: Kloppenborg, R. P., Nederkoorn, P. J., Geerlings, M. I., & van den Berg, E.
Affiliations: Utrecht University (NL)
From the Department of Neurology (R.P.K., P.J.N.), Academic Medical Center, Amsterdam; Julius Center for Health Sciences and Primary Care (R.P.K., M.I.G.) and Department of Neurology (R.P.K.), University Medical Center Utrecht; Experimental Psychology (E.v.d.B.), Helmholtz Institute, Utrecht University; and the Department of Neurology (E.v.d.B.), Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, the Netherlands.
ORCID: Nederkoorn, Paul J.
Geerlings, Mirjam I.
Venue: Neurology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2014-06-10
Volume: 82
Issue: 23
Pages: 2127-2138
ISSN: 0028-3878 (ISSN-L)
1526-632X
DOI: 10.1212/wnl.0000000000000505
OpenAlex: W2054692171
Cited by: 338
References: 64
Citations by year: 2026: 28 · 2025: 42 · 2024: 43 · 2023: 34 · 2022: 33 · 2021: 39 · 2020: 30 · 2019: 18 · 2018: 19 · 2017: 19 · 2016: 15 · 2015: 15 · 2014: 2
FWCI: 2.29
Type: journal article
Language: en
Open access: closed
Locations: Neurology (publishedVersion)
PubMed (publishedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Pure Amsterdam UMC (submittedVersion)
Topics: Health Sciences › Medicine › Clinical Neurology › Cerebrovascular and genetic disorders
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords: white matter hyperintensities, cognitive decline, cognitive domain, general intelligence, memory, processing speed, attention, executive function, brain MRI
MeSH terms: Cognition Disorders, Humans, Disease Progression, Leukoencephalopathies

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Presence and progression of white matter hyperintensities and cognition: A meta-analysis

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