Novel MRI Reveals Early Impact of Hypertension on Dementia Risk

Damian McNamara

June 26, 2018

Advanced MRI technology reveals previously undetectable brain damage induced by hypertension, a major risk factor for dementia.

Investigators, led by Lorenzo Carnevale, from the Department of Angiocardioneurology and Translational Medicine at the IRCCS Neuromed in Pozzilli, Italy, found "white matter (WM) fiber-tracking on MRI evidenced an early signature of damage in hypertensive patients when otherwise undetectable by conventional neuroimaging."

"Fiber tracking is an advanced analysis technique which can be performed on diffusion tensor imaging. Even though it is still not recommended by current clinical guidelines, many centers are equipped with the feasible technology and expertise to perform the analysis," Carnevale told Medscape Medical News.

"Though noninvasive and thus potentially applicable to the general hypertensive population, the systematic screening all hypertensive patients with this kind of routine may be a big effort for the clinical system," Carnevale added.

The study was published online June 12 in Cardiovascular Research.

Early Dementia Signature

Hypertension is often associated with adverse effects on the brain. The investigators note it's well known that "the vast majority of cases of Alzheimer's Disease and related dementia in elderly are not ascribable to genetic predisposition but rather to the chronic exposure to vascular risk factors in midlife."

Researchers looked for a way to predict these adverse effects at an earlier stage when microvascular changes take place. The current study builds on previous research demonstrating that white matter microstructural changes reflect the integrity and organization of white matter fiber bundles (Neuroimage. 2013;80:105-124; Biochim Biophys Acta. 2014;1842:2286-2297).  

For the study, investigators measured the cognitive performance of participants with no signs of dementia or structural brain changes on traditional imaging at baseline. They then repeated imaging with fiber-tracking technology and compared outcomes between those with and without hypertension.

The 42 outpatients enrolled in the current study between November 2014 and September 2017 included 23 hypertensive and 19 normotensive individuals.

Participants were 40 to 65 years old.

At baseline, a blinded neuroradiologist cleared all participants of macroscopic brain findings on conventional MRI on T1 and AX DP/T2 scans. Next, the same participants underwent advanced imaging with a 3T GE Signa Horizon scanner (General Electric Medical Systems).

The specific signature that investigators found for dementia risk among hypertensive patients involved deterioration of projection fibers of the right anterior thalamic radiation (ATR), association fibers of the right superior longitudinal fasciculus (SLF), and callosum fibers of the forceps minor (FMI) in the brain.

The ATR is a projection fiber that connects the thalamus's anterior nucleus to the anterior cingulate gyrus and frontal cortex, and ATR damage is associated with impaired memory.  

The SLF connects the cerebrum parietal and occipital and temporal lobes with the ipsilateral frontal cortices. It facilitates the formation of a bidirectional neural network necessary for cognitive functions, such as attention, memory, emotions, and language.

Within these tracts, the hypertensive group displayed a significant decrease in fractional anisotropy, a concomitant increase in mean diffusivity, and a significant alteration of radial diffusivity and axial diffusivity.

The FMI is a fiber bundle that connects the frontal lobes' lateral and medial surfaces, crosses the midline via the genu of the corpus callosum, and has been linked to processing speed tasks.

The observed damage  to these fibers correlated to decreases in neuropsychiatry test results among the hypertensive group.

A blinded, certified psychologist tested cognitive function and looked for any impairment of activities of daily living at baseline. Participants then underwent Montreal Cognitive Assessment (MoCA) neuropsychological testing. Hypertensive patients had significantly greater impairments on MoCA performance compared with the normotensive group.

When the investigators analyzed specific MoCA cognitive subdomains, hypertensive participants displayed significantly impaired memory, executive function, attention, and language domains.

In addition, the hypertensive group scored worse on verbal paired-associate learning, a finding that suggests they face challenges in retaining new information through working memory. Hypertension also appeared to impair executive function measure on the Stroop test.

Table. Cognitive Assessment Findings

Mean Scores Normotensive Group Hypertensive Group P Value
Instrumental activities of daily living 7.7 7.65 .618
MoCA 26.00 22.08 <.001
Semantic verbal fluency 49.47 44.08 .129
Paired associate learning 13.78 9.6 <.01
Stroop color word test 0.21 0.85 <.05
Stroop fluency test (mean time) 16.45 25.5 <.001

 All hypertensive participants were taking antihypertensive therapy. The study therefore included "a sample of patients with an adequate range of blood pressure control, suggesting that an efficient anti-hypertensive therapy is not sufficient to exclude the onset of vascular dementia or protect the brain from white matter microstructural damage," the researchers note.

Opportunity for Early Intervention?

The findings support the possibility that noninvasive advanced brain imaging coupled with cognitive assessment could support the early prediction of long-term deficits in patients with hypertension, the authors write.

Evaluation of white matter tract changes using 3T MRI and fiber-tract probabilistic analysis is a strength of the study, they note. In addition, because they only included patients without dementia or signs of brain damage on conventional MRI at baseline, it allowed them to predict cognitive decline at an early stage.

However, the strict entry criteria also limited the sample size. In addition, the study design did not allow assessment of evolution of the damage in hypertensive patients over time. Future studies are warranted to evaluate longitudinal changes in white matter changes and dementia.

The investigators would like to study how lifestyle and dietary habits may complement clinical, tractographical, and cognitive data in the future, with an ultimate aim of tailoring antihypertensive treatment to reduce dementia risk on an individual basis.

"Our results point out a big issue in current cardiovascular diseases treatment: We can't ignore the brain," Carnevale said. "Current therapies are not tailored to ensure at the same time cardiovascular protection and cognitive function protection. We must seek new therapies that can prove their efficacy in achieving both targets.

"The next step is to expand our 'biomarker' with more personalized data, with advanced immunological analysis from blood samples and genetic profiling."

"Moreover, it would be really important to adopt advanced and multidisciplinary diagnosis tools, such as advanced MRI or cognitive profiling, for subjects with high risk of developing dementia," he added.

Novel Imaging, New Insight

Commenting on the findings for Medscape Medical News is David S. Knopman, MD, a clinical neurologist who researches late-life cognitive disorders at Mayo Clinic in Rochester, Minnesota.

"This rather small study of 42 middle-aged patients — 23 of whom had hypertension — showed that the MR imaging technique of diffusion tensor imaging (or DTI) with probabilistic fiber-tracking revealed changes in cerebral white matter in the hypertensives. These DTI changes occurred in the absence of white matter hyperintensities seen on conventional T2-weighted images," he said.

Hypertension is well known to be associated with excess white matter hyperintensities on MRI, and hypertension in midlife is also well established as a risk factor for later-life dementia, Knopman noted.

"While the findings here are not novel, they provide insight into the very long premonitory period in which hypertension might be causing subclinical brain injury that itself is part of the substrate for later-life dementia. The main thrust of this article is that of highlighting the value of the novel imaging technique," he added.

A grant from the Italian Ministry of Health supported the research. Carnevale and Knopman have disclosed no relevant financial relationships.

Cardiovasc Res. Published online June 12, 2018. Abstract

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