Risk factors and clinical significance of neurodegenerative co-pathologies in symptomatic cerebral small vessel disease

J Neurol. 2025 Apr 18;272(5):349. doi: 10.1007/s00415-025-13087-z.

Abstract

Background: Cerebral small vessel disease (CSVD) often coexists with neurodegenerative pathologies, yet their role remains underexplored. This study aims to determine their prevalence, risk factors, and cognitive effects in patients with deep perforator arteriopathy (DPA) or cerebral amyloid angiopathy (CAA) using the biomarker-based ATN classification.

Methods: In this cross-sectional study 186 patients (median age 75 years, 41% females, 111 with probable CAA, 75 with DPA) underwent MRI for analysis of CSVD severity and etiology, and lumbar puncture for analysis of cerebrospinal fluid amyloid-β 42/40 ratio, phosphorylated-tau, total-tau and neurofilament light. ATN profiles were related to clinical characteristics, MRI markers and cognitive performance in multivariate regression models.

Results: Among CSVD patients, 30% had normal biomarkers (A-T-N-), 33% were within the AD pathology continuum (A + T ± N ± : 47% in CAA vs. 13% in DPA, p < .001), and 37% showed non-AD pathological changes (A-T ± N + : 53% in DPA vs. 25% in CAA, p < .001). The AD pathology continuum was associated with a severe lobar hemorrhagic phenotype and cognitive impairment, while non-AD pathological change was related to CSVD severity, history of stroke and similarly cognitive impairment. Both pathological ATN profiles were further related to lower MMSE scores (A + T ± N ± : B = - 3.3, p = .006; A-T ± N + : B = - 2.7, p = .021).

Conclusions: Using biomarkers, this study confirms in vivo that CSVD frequently co-occurs with neurodegenerative pathologies, exerting detrimental effects on cognitive health.

Keywords: ATN classification; Alzheimer's disease pathology; Cerebral amyloid angiopathy; Cerebral small vessel disease; Deep perforator arteriopathy; Non-AD pathological change.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Biomarkers / cerebrospinal fluid
  • Cerebral Amyloid Angiopathy* / cerebrospinal fluid
  • Cerebral Amyloid Angiopathy* / complications
  • Cerebral Amyloid Angiopathy* / diagnostic imaging
  • Cerebral Amyloid Angiopathy* / epidemiology
  • Cerebral Amyloid Angiopathy* / pathology
  • Cerebral Small Vessel Diseases* / cerebrospinal fluid
  • Cerebral Small Vessel Diseases* / complications
  • Cerebral Small Vessel Diseases* / diagnostic imaging
  • Cerebral Small Vessel Diseases* / epidemiology
  • Cerebral Small Vessel Diseases* / pathology
  • Clinical Relevance
  • Cognitive Dysfunction / epidemiology
  • Cross-Sectional Studies
  • Female
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Neurodegenerative Diseases* / cerebrospinal fluid
  • Neurodegenerative Diseases* / epidemiology
  • Neurodegenerative Diseases* / pathology
  • Neurofilament Proteins / cerebrospinal fluid
  • Risk Factors
  • tau Proteins / cerebrospinal fluid

Substances

  • Amyloid beta-Peptides
  • Biomarkers
  • tau Proteins
  • Neurofilament Proteins