Periventricular White Matter Hyperintensities May Signify Alzheimer’s Risk

Cortical arterial disease may correlate to cerebral beta amyloid accumulation.

Quantification of periventricular white matter hyperintensities (PVWMH) may help identify people at higher risk of Alzheimer’s disease (AD), according to results from a study published in Neurology.

Investigators from the global multicenter Alzheimer’s Disease Neuroimaging Initiative (ADNI) examined PVWMH for quantitative measures of cortical arterial disease for its correlation to cerebral beta amyloid accumulation, a known biomarker for AD.

Cerebral small vessel disease (SVD) was found in previous studies to be present in as many as 80% of people with AD, and was associated with a more rapid progression to cognitive decline,2 possibly due to disruptions in intersititial fluid flow facilitating beta amyloid clearance.3 As the periventricular area of the brain is most vulnerable to damage of the cortical arteries associated with distal hypoperfusion that may result in PVWMH, the study focused on measuring cortical arterial disease in this region.4

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A total of 698 participants (435 of whom were defined as having mild cognitive impairment (MCI) at baseline, compared with 263 with normal cognition (NC)) were evaluated using magnetic resonance imaging (MRI), Fluorine-18 florbetapir-PET scanning, and analysis of cerebrospinal fluid (CSF) for the presence of beta amyloid, tau, and phosphor-tau.

Increased PVWMH burden in the parietal, occipital, and frontal regions of the brain all correlated with reduced levels of beta amyloid in the CSF. Regression analysis showed that parietal burden and occipital grade were associated with CSF-Aß positivity, independent of known predictive factors, including age, having the APOE allele, and vascular risk factors, while frontal PVWMH was not.  As the frontal region is a less common site for cerebral amyloid angiopathy (CAA), the investigators ascribed this finding to CAA-driven cortical arterial disease.

Clear associations between PVWMH and FDG-PET hypointensities were found in the angular, temporal, and posterior cingulate regions of the brain, which are known to be vulnerable to beta amyloid accumulation.

“PVWMH were associated with reduced FDG-PET uptake independent of the extent of cerebral amyloid accumulation,” reported lead author Michael Marnane, MD, PhD, MRCPI, a Postdoctoral Fellow in the Alzheimer’s Disease and Related Dementias Program at the University of British Columbia Hospital in Vancouver, BC.  “The mechanisms underlying this observation are not clear from the current study but warrant further investigation with potential to identify novel vascular therapeutic targets.”

The findings indicated that measurement of PVWMH provided markers of risk for cognitive decline as a result of beta amyloid accumulation as well as other mechanisms. Once validated in other cohorts, PVWMH quantification could be used to identify suitable patients for clinical trials of anti-amyloid therapies.

“The association between increased burden of PVWMH and elevated cerebral amyloid raises interesting questions with regard to the interpretation of previous clinical trials of anti-amyloid therapies,” Dr Marnane said.  “Historically, many such trials excluded individuals with prominent vascular disease. Whether people in this subgroup are more likely to benefit from anti-amyloid interventions or instead are vulnerable to adverse reactions such as ARIA and unlikely to benefit remains to be clarified.”


  1. Marnane M, Al-jawadi OO, Mortazavi S, et al. Periventricular hyperintensities are associated with elevated cerebral amyloid. Neurology. 2016; doi:10.1212/WNL.0000000000002352.
  2. Thal DR, Attems J, Ewers M. Spreading of amyloid, tau, and microvasculaar pathology in Alzheimer’s disease: findings from neuropathological and neuroimaging studies. J Alzheimers Dis. 2014;42:S421-S429.
  3. Weller RO, Hawkes CA, Kalaria RN, et al. White matter changes in dementia: role of impaired drainage of interstitial fluid. Brain Pathol. 2014;25:63-78.
  4. Moody DM, Bell MA, Challa VR.  Features of the cerebral vascular pattern that predict vulnerability to perfusion or oxygenation deficiency: an anatomic study. Am J Neuroradiol. 1990;11:431-439.