Advanced Imaging May Reveal Onset of Cognitive Impairment

An exploratory study that revealed differences in neurotransmitter levels in regions of the brain commonly linked to cognition sets the stage for future research to better understand the "inner workings" of mild cognitive impairment (MCI) and progression to Alzheimer disease (AD).

The novel findings come courtesy of magnetic resonance spectroscopy (MRS) with advanced 7 Tesla (7T) technology. This approach shows levels of gamma-aminobutyric acid (GABA), glutathione, and other neurotransmitters in brain regions of interest with greater precision than previous, lower-strength imaging systems.

Results showed significant differences in neurotransmitters and other factors in the anterior cingulate cortex (ACC) and the posterior cingulate cortex (PCC) between 13 people with MCI and 13 healthy control persons.

Changes in neurotransmitters in MCI "could be a promising way to find out more about the inner workings of the disease and how it proceeds," lead author Georg Oeltzschner, PhD, a postdoctoral fellow in the Russell H. Morgan Department of Radiology and Radiological Science at the Johns Hopkins University School of Medicine in Baltimore, Maryland, told Medscape Medical News.

The study was published in the January issue of Neurobiology of Aging.

Neuronal Loss Visible

"We do know from a lot of studies that local neurotransmitter levels can be related to measures of behavioral outcomes, such as memory, reaction time, and things like that," Oeltzschner said. "These relationships can be region specific," he said.

When neurotransmitter levels change locally, the macroscopic communication within or between brain regions also can vary, he added.

The investigators chose the ACC and the PCC of the involvement of these regions in executive function and mood regulation. During the onset of MCI and AD, these regions exhibit increased deposition of beta-amyloid and tau protein.

It's unclear how nuances in neurotransmitters contribute to loss of cognitive and executive function in patients with MCI.

However, the investigators speculate that "abnormal levels of GABA and glutamate may reflect disturbed inhibitory and excitatory neurotransmission, which primarily shape cortical information processing."

To learn more, the investigators examined neurocognitive testing performance, spectroscopy findings, and other factors.

The patients with MCI included three women and 10 men (mean age, 70 years); the control group consisted of seven women and six men (mean age, 64 years). Because of the disparity in the ages of the participants, the investigators controlled for age as a covariate.

All participants underwent a physical exam, a neurologic exam, and a structured clinical interview that was performed by a clinical psychologist. They also were assessed with the Clinical Dementia Rating (CDR) scale, the Mini–Mental State Examination (MMSE), and other measures.

Mean MMSE scores were 1.7 in the MCI group vs 28.7 in the healthy control group. This difference was statistically significant (P < .01). Mean scores on the Delis-Kaplan Executive Function System (D-KEFS) assessment were 12.5 in the MCI group and 42.8 for the healthy control participants (P = .073).

Mean California Verbal Learning Test (CVLT) results, calculated as the sum of the first five trials, were 10.3 in the MCI group and 55.5 among the healthy control persons (P < .001).

Comparisons between the MCI group and the control group revealed statistically significant differences in the ratios of neurotransmitters and other relevant factors to a reference compound, total creatine (tCr). Incorporating the reference compound helped researchers assign the observed changes to neuronal loss associated with MCI and not with other mechanisms.

Counters Previous Research

For example, the ratio of GABA to tCr was significantly lower among MCI patients in comparison with control persons. This finding was significant for both the ACC and PCC regions of the brain (P < .01). However, the investigators did not find any relationship between GABA/tCr levels and cognitive scores.

Decreased GABA in the ACC suggests that disturbed homeostasis of this neurotransmitter in patients with MCI may also occur in cortical regions other than the PCC, which carries implications for cognitive function, the researchers note.

This finding, which counters previous study results, and may be due to the greater precision of the scanner used to obtain the images — the 7T Philips Achieva scanner (Philips Healthcare, Best, the Netherlands) with a 32-channel receive and quadrature transmit head coil (Nova Medical, Wilmington, Massachusetts).

The MCI group also had significantly decreased levels of glutamate/tCr. This outcome was significant in the PCC (P < 0.05) in comparison with the control persons. In addition, the group with MCI had significantly lower levels of a marker of neuronal integrity called N-acetylaspartate (NAA) relative to tCr, particularly in the PCC (P < .05).

Furthermore, the patients with MCI were found to have a significantly higher ratio of the osmolyte myo-inositol to total creatine (mI/tCr) in the anterior cingulate complex compared to the control persons (P < .01).

MMSE test scores showed a negative correlation with mI/tCr in the ACC (P < .01) and the PCC (P < .05).

D-KEFS scores positively correlated with the antioxidant glutathione/tCr in the PCC (P < .01).

CVLT scores positively correlated with glutamate/tCr (PCC, P <.05) and NAA/tCr (PCC, P < .05). These scores negatively correlated with mI/tCr in both the ACC and the PCC (for each, P < .05).

"The observed correlation between PCC glutamate/tCr and CVLT scores may suggest that disturbed glutamate neurotransmission is at least partly contributing to memory impairment in MCI," the researchers note.

7-Tesla Device

"To the best of our knowledge, this is the first study to use magnetic resonance spectroscopy at 7T field strength to study metabolic changes in MCI patients, including quantification of the low-concentration metabolites GABA, GSH [glutathione] and NAAG [N-acetylaspartylglutamate] in a single session," the researchers note.

"Taken together, these findings indicate a promising link between several pathophysiological MCI/AD mechanisms and cognitive outcome, and certainly warrant further investigation in terms of regional and functional specificity," they add.

The FDA cleared the first 7-Tesla device for use in the United States in 2017. Oeltzschner estimates that fewer than 100 systems exist globally. "Most of them are dedicated to research," he added.

For this reason, Oeltzschner, study coauthor Richard Edden, PhD, and their colleagues are developing methodology for devices of 3-Tesla field strength, which are much more common than 7-Tesla machines. "The obvious massive advantage would be that these methods would become available to a lot more researchers, given the low number of 7T machines," said Oeltzschner.

The study's limitations, said Oeltzschner, include the fact that it involved a small number of participants who had a wide range of ages and that it was cross-sectional in nature.

He added that neurotransmitters are not a very specific sign of MCI at this point.

"To really solidify these findings, it would be great if we had a much larger sample size and longitudinal data," he added. "The dream would be to find a neurochemical signature [for MCI] using this spectroscopy technique."

Unique Contribution

Commenting on the findings of Medscape Medical News, Sami Ouanes, MD, Department of Psychiatry, Hospital of Cery, University Hospital of Lausanne, Switzerland, noted that this is "one of very few studies investigating the in vivo levels of such a large number of neurotransmitters, oxidative stress, and neuronal markers in patients with...mild cognitive impairment due to probable Alzheimer's disease.

"Most of our knowledge about these markers in MCI and AD previously came from post mortem studies or from animal studies," added Ouanes, who is also affiliated with the Department of Psychiatry at Hamad Medical Corporation in Doha, Qatar.

"What is also interesting is that authors tried to link these markers to the clinical cognitive performance and to the amyloid PET-scan findings," he said. Whereas GABA was decreased in both the ACC and the PCC in patients with MCI, the study failed to find any associations with any clinical parameters, he added.

"The links observed between glutamate deficit and verbal episodic memory performance on the one hand and between verbal fluency and oxidative stress markers on the other hand may suggest that targeting the glutamatergic system and the redox system may improve some of the symptoms in patients with MCI/Alzheimer disease," he said.

The lack of statistical power because of the small sample size, as well as the cross-sectional design of the study, are limitations to keep in mind, Ouanes added. "Such a design cannot allow us to draw any causality links," he said.

Nevertheless, he said, the study "is a step forward towards a better understanding of the interrelationships between disrupted neurotransmission, oxidative stress, amyloid deposits, and clinical findings in MCI/Alzheimer disease. But longitudinal studies with larger sample sizes are still mostly lacking, and thus really needed, in this regard."

The study was supported by grants from the National Institutes of Health. Oeltzschner and Ouanes had disclosed no relevant financial relationships.

Neurobiol Aging. 2019;73:2011-2018. Full text

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