Study: MRI weaves clearer picture of Alzheimers

Researchers have found that individuals carrying a particular gene variant displayed structural brain differences on MRI consistent with Alzheimer's disease as they reached older ages, connecting dispersed findings and showing promise for early risk evaluation of Alzheimer’s, according to a study published in the February issue of the Archives of General Psychiatry.

Variation in the brain-derived neurotrophic factor (BDNF) genetic polymorophism Val66Met has been shown to be related to memory performance in young adults and cognitive performance in elderly individuals. Moreover, neurons containing neurofibrillary tangles, a hallmark of Alzheimer’s disease, have demonstrated reduced BDNF expression, leading researchers to suspect that the “BDNF gene variation may be a genetic susceptibility mechanism for AD [Alzheimer's disease],” wrote Aristotle N. Voineskos, MD, PhD, of the department of psychiatry, Geriatric Mental Health Program, at the Centre for Addiction and Mental Health in Toronto, and co-authors.

Voineskos and colleagues sought to shed light on several lines of cognitive and neuroimaging evidence suggesting a role for BDNF in late-onset Alzheimer’s, which accounts for 90 to 95 percent of cases of the disease. To do so, the researchers combined high-resolution MRI, diffusion tensor MRI and cognitive testing to investigate the effect of the BDNF gene and age on neural structures and cognitive functions that are disrupted under Alzheimer’s, hypothesizing relationships between BDNF Val66Met and age with cortical thickness, white matter and episodic memory.

The subjects were divided into two groups, one consisting of 28 Met allele carriers and the other with 41 Val Val homozygotes. All 69 participants were cognitively healthy and the two groups displayed no significant differences in IQ, education and other AD-linked factors.

The BDNF genotype was correlated with reduced cortical thickness at several regions in the temporal lobe for both groups. BDNF was also associated with reduced microstructural white matter tract integrity of the cingulum bundle, inferior longitudinal fasisculus and arcuate fasciculus. Finally, BDNF was correlated with lower episodic memory (figure recall) scores.

All of these statistically significant relationships were observed as BDNF interacted with age, such that the negative relationships were seen with increasing age, while controlling for age’s independent effects on these outcomes.

“After stratification of our analyses for sex, similar patterns in men and women, as in the overall analysis, were observed for Met allele carriers and for Val/Val individuals, in which Met allele carriers were at risk in earlier life and Val/Val individuals in later life for reduced cortical thickness, white matter integrity, and episodic memory performance,” the authors explained.

“We found that the BDNF Val66Met polymorphism interacts with age in a biologically convergent manner to predict variation in at-risk neural structures and cognitive functions of AD in healthy humans,” Voineskos and colleagues continued.

The researchers measured their discoveries in view of a number of related findings from previous research, including studies implicating BDNF in mood disorders, temporal lobe structure, white matter tract integrity, episodic memory and additional structural brain features, all of which have been linked to Alzheimer’s. “Multiple lines of evidence implicate BDNF in the AD process,” the authors claimed.

Voineskos and colleagues considered their study important in reproducing and tying together many of these nonreplicated findings, an inference they attributed to their integration of genetic indicators with both cognitive performance and brain structure on MRI. They emphasized, however, that the relationships they observed based on BDNF and age were linked to phenotypical indicators of Alzheimer's disease in order to advance early detection; no Alzheimer’s patients were included in the study.

“The convergent pattern of our findings across gray matter, white matter, and cognitive performance provide a more convincing picture of the effect of the BDNF Val66Met polymorphism on an intermediate phenotype related to AD than any one of these [previous] findings alone,” Voineskos and colleagues argued. “Our findings suggest that the BDNF gene may be a susceptibility mechanism for AD and highlight a critical alternative pathway in this neurodegenerative disorder.”