Tract-specific white matter hyperintensities and neuropsychiatric syndromes: a multicentre memory clinic study

Topic: Brain proteins, microglia and lab models

Among 2935 patients (50.4% women; mean age=72.2 years; 19.8% subjective cognitive impairment, 39.8% mild cognitive impairment, and 40.4% dementia), larger WMH volume within projection fibres (B=0.24, SE=0.10, p=0.013) was associated with greater apathy. Larger WMH volume within association (B=0.31, SE=0.12, p=0.009), commissural (B=0.47, SE=0.17, p=0.006) and projection (B=0.39, SE=0.16, p=0.016) fibres was associated with greater hyperactivity, driven by the inferior fronto-occipital fasciculus (B=0.50, SE=0.18, p=0.006), forceps major (B=0.48, SE=0.18, p=0.009) and anterior thalamic radiation (B=0.49, SE=0.19, p=0.011), respectively. Larger WMH volume in the uncinate fasciculus (B=1.82, SE=0.67, p=0.005) and forceps minor (B=0.61, SE=0.19, p=0.001) were additionally associated with greater apathy. No associations with affective and psychosis were observed. Tract-syndrome specificity of WMH burden with apathy and hyperactivity suggests that disruption of strategic neuronal pathways may be a potential mechanism through which small vessel disease affects emotional and behavioural regulation in memory clinic patients.

@article{kan2025-39761997,
  author  = {Kan, Cheuk Ni and Coenen, Mirthe and Xu, Xin Yi and Hilal, Saima and Barkhof, Frederik and Benke, Thomas and Dal‐Bianco, Peter and DeCarli, Charles S and others},
  title   = {{Tract-specific white matter hyperintensities and neuropsychiatric syndromes: a multicentre memory clinic study}},
  journal = {Journal of Neurology Neurosurgery \& Psychiatry},
  year    = {2025},
  doi     = {10.1136/jnnp-2024-334264},
  pmid    = {39761997},
  url     = {https://doi.org/10.1136/jnnp-2024-334264}
}

Key findings

• Among 2935 patients (50.4% women; mean age=72.2 years; 19.8% subjective cognitive impairment, 39.8% mild cognitive impairment, and 40.4% dementia), larger WMH volume within projection fibres (B=0.24, SE=0.10, p=0.013) was associated with greater apathy.
• Larger WMH volume within association (B=0.31, SE=0.12, p=0.009), commissural (B=0.47, SE=0.17, p=0.006) and projection (B=0.39, SE=0.16, p=0.016) fibres was associated with greater hyperactivity, driven by the inferior fronto-occipital fasciculus (B=0.50, SE=0.18, p=0.006), forceps major (B=0.48, SE=0.18, p=0.009) and anterior thalamic radiation (B=0.49, SE=0.19, p=0.011), respectively.
• Larger WMH volume in the uncinate fasciculus (B=1.82, SE=0.67, p=0.005) and forceps minor (B=0.61, SE=0.19, p=0.001) were additionally associated with greater apathy.
• No associations with affective and psychosis were observed.
• Tract-syndrome specificity of WMH burden with apathy and hyperactivity suggests that disruption of strategic neuronal pathways may be a potential mechanism through which small vessel disease affects emotional and behavioural regulation in memory clinic patients.

Why it matters

In memory clinic patients, greater white matter hyperintensity volume in specific fibre tracts was linked to more apathy and hyperactivity, but not to affective or psychosis symptoms. This suggests that damage to particular brain pathways from small vessel disease may contribute to these behavioural symptoms, though the study does not test any treatment.

Study details

• Participants2,935
• Effect size50.4%; 19.8%; 39.8%
• Evidence strengthLow

Read the original

• DOI: 10.1136/jnnp-2024-334264
• PubMed: 39761997
• Original source →
• Free full text: Pure Amsterdam UMC →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study JAMA · 2002-09-01 · usefulness score 78/100 · How common it is
• Neuropsychiatric symptoms associated with cerebral small vessel disease: a systematic review and meta-analysis The lancet. Psychiatry · 2021-02-01 · usefulness score 69/100 · Prevention and risk
• Brain mechanisms underlying neuropsychiatric symptoms in Alzheimer's disease: a systematic review of symptom-general and -specific lesion patterns Molecular neurodegeneration · 2021-06-07 · usefulness score 60/100 · Mild cognitive impairment
• Affective and emotional dysregulation as pre-dementia risk markers: exploring the mild behavioral impairment symptoms of depression, anxiety, irritability, and euphoria International psychogeriatrics · 2017-09-13 · usefulness score 50/100 · Prevention and risk
• Cerebral white matter: neuroanatomy, clinical neurology, and neurobehavioral correlates Annals of the New York Academy of Sciences · 2008-10-01 · usefulness score 49/100 · Getting a diagnosis

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