Dissociable effects of Alzheimer disease and white matter hyperintensities on brain metabolism

JAMA Neurol. 2013 Aug;70(8):1039-45. doi: 10.1001/jamaneurol.2013.1878.


Importance: Cerebrovascular disease and Alzheimer disease (AD) frequently co-occur and seem to act through different pathways in producing dementia.

Objective: To examine cerebrovascular disease and AD markers in relation to brain glucose metabolism in patients with mild cognitive impairment.

Design and setting: Cohort study among the Alzheimer Disease Neuroimaging Initiative clinical sites in the United States and Canada.

Participants: Two hundred three patients having amnestic mild cognitive impairment (74 of whom converted to AD) with serial imaging during a 3-year follow-up period.

Main outcomes and measures: Quantified white matter hyperintensities (WMHs) represented cerebrovascular disease, and cerebrospinal fluid β-amyloid represented AD pathology. Brain glucose metabolism in temporoparietal and frontal brain regions was measured using positron emission tomography with fluorodeoxyglucose F18.

Results: In converters, greater WMHs were associated with decreased frontal metabolism (-0.048; 95% CI, -0.067 to -0.029) but not temporoparietal metabolism (0.010; 95% CI, -0.010 to 0.030). Greater cerebrospinal fluid β-amyloid (per 10-pg/mL increase) was associated with increased temporoparietal metabolism (0.005; 95% CI, 0.000-0.010) but not frontal metabolism (0.002; 95% CI, -0.004 to 0.007) in the same patients. In nonconverters, similar relationships were observed except for a positive association of greater WMHs with increased temporoparietal metabolism (0.051; 95% CI, 0.027-0.076).

Conclusions and relevance: The dissociation of WMHs and cerebrospinal fluid β-amyloid in relation to regional glucose metabolism suggests that these pathologic conditions operate through different and independent pathways in AD that reflect dysfunction in different brain systems. The positive association of greater WMHs with temporoparietal metabolism suggests that these pathologic processes do not co-occur in nonconverters.

Publication types

  • Comparative Study
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Amyloid beta-Peptides / metabolism
  • Biomarkers / cerebrospinal fluid
  • Biomarkers / metabolism
  • Brain Injuries / cerebrospinal fluid
  • Brain Injuries / metabolism*
  • Brain Injuries / pathology*
  • Cerebrovascular Disorders / cerebrospinal fluid
  • Cerebrovascular Disorders / metabolism
  • Cerebrovascular Disorders / pathology
  • Cognitive Dysfunction / cerebrospinal fluid
  • Cognitive Dysfunction / metabolism
  • Cognitive Dysfunction / pathology
  • Cohort Studies
  • Female
  • Follow-Up Studies
  • Humans
  • Leukoencephalopathies / cerebrospinal fluid
  • Leukoencephalopathies / metabolism*
  • Leukoencephalopathies / pathology*
  • Male
  • Middle Aged


  • Amyloid beta-Peptides
  • Biomarkers