Dual-target PET teases apart dementia class

A PET imaging technique gleaning information about both dopamine terminal integrity and amyloid burden in the brain may help researchers classify forms of mild cognitive impairment (MCI) and predict dementia risk, according to a study published online April 9 in The Journal of Nuclear Medicine.

Roger L. Albin, MD, a neurologist from the University of Michigan in Ann Arbor, Mich., and colleagues, devised a molecular-imaging based system of classification for mild cognitive impairment as it progresses into three subtypes of dementia: Alzheimer’s disease, Lewy body dementia (LBD) and frontotemporal dementia (FTD). The objectives of the research were to assess the technique's ability to determine the probable cause of MCI and to predict development of dementia.

PET imaging to determine cause of MCI was performed with two biomarkers, C-11 dihydotetrabenazine to measure striatal dopamine terminal integrity and C-11 Pittsburgh compound B (C-11 PiB) to quantify cerebral amyloid deposition. Amyloid burden has long had a positive association with onset of Alzheimer’s disease and significant loss of nigrostriatal dopaminergic terminals is a strong sign of LBD. Results of this prospective and cross-sectional study showed clear patterns of amyloid deposition and denervation of the nigrosriatal dopamine pathways for each respective subtype of MCI.

“These results, and others, indicate that molecular imaging with amyloid and nigrostriatal dopamine terminal ligands may identify characteristic pathologic features of neurodegenerative dementias,” wrote the authors.

A total of 27 participants with MCI were involved in the research. Follow-up at a mean of three years revealed that 18 MCI patients had progressed to dementia. Subjects with higher uptake of C-11 PiB and normal distribution of C-11 dihydotetrabenazine were considered to have Alzheimer’s dementia. Those with lower striatal C-11 dihydotetrabenazine uptake were classifed LBD. Finally, those with normal binding of both biomarkers were labeled FTD. Results of PET imaging revealed 18 subjects with Alzheimer’s pathology, seven with signs of FTD and two patients with the neural characteristics of LBD. For each subtype of MCI, about two-thirds developed dementia. A model for classifying types of MCI could improve the quality of future clinical trials, according to researchers.

“Accurate, pathologically based classification of MCI subjects would facilitate enrollment of more homogeneous subject populations and also increase statistical power in disease-modifying trials,” wrote Albin et al. “Amyloid imaging and nigrostriatal dopamine terminal imaging are well validated by postmortem studies as biomarkers for cerebral beta-amyloid deposition and LBD.”

The researchers listed several caveats. Risk of misclassifcation was a potential for FTD, which also can present striatal denervation. Vascular disease and tau formations can lead to FTD, which this technique would not indicate. Therefore, FTD-specific ligands would improve classification for this subtype.

“Although conventional, this classification approach inevitably obscures some of the complexities of overlapping pathologies contributing to the clinical features of dementing illnesses,” the researchers added. “Some FTD cases, for example, notably those associated with tau mutations, exhibit significant parkinsonism and loss of nigrostriatal neurons.”

Another issue was the potential for those with LBD pathology to experience quick progression of striatal dopaminergic innervation when converting to full onset dementia.

“This finding raises the interesting possibility that dopamine terminal PET or SPECT imaging, although generally thought to be useful in establishing a diagnosis of LBD in individuals in established dementia, may be insensitive in precursor states like MCI,” the authors wrote. “Larger prospective studies are required to address this question.”