Alzheimer’s disease

Brain Lesions May Play Role in Alzheimer’s

White matter hyperintensities may be a “second hit” that combines with beta-amyloid to produce Alzheimer’s disease, researchers found.
In a cohort of participants in the Alzheimer’s Disease Neuroimaging Initiative, the two factors were independent predictors of Alzheimer’s disease, according to Adam Brickman, PhD, of Columbia University in New York City, and colleagues.
But among people with elevated amyloid levels, those with the disease had higher volumes of white matter hyperintensities or small brain lesions detectable on MRI, they reported online in JAMA Neurology.
Among participants with mild cognitive impairment, both factors predicted the transition to Alzheimer’s disease, they explained.
“White matter hyperintensities contribute to the presentation of Alzheimer’s disease and, in the context of significant amyloid deposition, may provide a second hit necessary for the clinical manifestation of the disease,” they wrote.
Current models of the disease place the emphasis on the accumulation of beta-amyloid in the brain, but some people remain cognitively healthy despite amyloidosis.
That suggests that amyloid deposition may be necessary to cause the disease, but it may not be all that’s required, the authors said, adding that vascular factors have been consistently linked to Alzheimer’s disease.
They looked at data from 100 older participants in the neuroimaging project, 21 who were cognitively normal, 59 with mild cognitive impairment, and 20 diagnosed with Alzheimer’s disease.
The researchers used MRI to establish the volume of white mater hyperintensities and PET studies with the Pittsburgh Compound B (PIB) tracer to quantify beta-amyloid positivity.
Of the 41 scans from patients with Alzheimer’s disease and control subjects, 28 (68%) were classified as PIB positive. Of this 68%, 11 were clinically defined as normal control subjects and the remaining were clinically defined as having Alzheimer’s disease.
Of the 13 without amyloidosis, just three met clinical criteria for Alzheimer’s, Brickman and colleagues reported.
A logistic regression analysis showed that higher lesion volume (P=0.02) and higher beta-amyloid (P=0.049) were each significantly and independently associated with an Alzheimer’s diagnosis.
When the analysis was restricted just to participants with amyloidosis, increased lesion volume was also significantly associated with an Alzheimer’s diagnosis (P=0.002).
The 59 participants with mild cognitive impairment were followed 29.73 months on average; during follow-up, 22 converted to Alzheimer’s disease.
Of the 59 at baseline, seven had low amyloid and low lesion volume, 11 had low amyloid but high lesion volume, 17 had amyloidosis but low lesion volume, and 24 were high in both factors.
The proportion of participants who converted to Alzheimer’s during follow-up increased monotonically across the four groups, Brickman and colleagues reported, and the linear-by-linear association was significant (P=0.03).
One implication of the findings is that modifying the risk factors for white matter hyperintensities might help prevent the clinical syndrome of Alzheimer’s, the authors noted. But they also cautioned that the study is small and replication in a larger sample is needed.
Nevertheless, they concluded, “it is becoming clear from studies such as this one and others that vascular factors are quite important in the pathogenesis of the (Alzheimer’s) phenotype.”
Other recent research has also linked vascular factors to the risk of cognitive decline. Earlier this month, researchers reported that vascular brain injury appears to play a role in the development of mild cognitive impairment, but amyloidosis does not.
The findings have “important clinical implications” given that up to 30% of cognitively healthy older people have elevated amyloid levels, commented Karen Rodrigue, PhD, of the University of Texas at Dallas.
While the exact contribution of small vessel cerebrovascular disease to Alzheimer’s pathology remains unclear, “the presence of vascular risk exacerbates cognitive aging,” she argued in an accompanying editorial.
It follows that “better and earlier control” of the manifestations of cerebrovascular disease is likely to pay off in better cognitive and cardiovascular health, she commented.

by Michael Smith, North American Correspondent
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania
Primary source: JAMA Neurology
Source reference: Provenzano FA, et al “White matter hyperintensities and cerebral amyloidosis: necessary and sufficient for clinical expression of Alzheimer disease?” Arch Neurol 2013; 70: 1-7.
Additional source: JAMA Neurology
Source reference: odrigue KM “Contribution of cerebrovascular health to the diagnosis of Alzheimer disease” Arch Neurol 2013; 70.