First Amyloid, Then Tau, Then Dementia

by Kristina Fiori for MedPage Today:

In one of the first studies of its kind, tau imaging was able to distinguish patients with Alzheimer's disease from those without, researchers reported.

In a study of 59 patients, [18F]-AV-1451 PET imaging distinguished Alzheimer's patients from those with normal cognition (AUC 0.89 to 0.98), and elevated tau was tied to volume loss in the hippocampus and cerebral cortex, Beau Ances, MD, PhD, of Washington University in St. Louis, and colleagues reported online in JAMA Neurology.

The findings suggest that tau imaging may be useful for disease staging in Alzheimer's, and that interactions between amyloid and tau may be key to the neurodegeneration and cognitive impairment seen in the disease.

"This places tau imaging nicely within the context of other biomarkers for Alzheimer's disease," Ances told MedPage Today.

Liana Apostolova, MD, of Indiana University, who wasn't involved in the study, told MedPage Today that the results fit nicely in line with an expert consensus published in Neurology earlier this month that suggested an "A/T/N" classification scheme for Alzheimer's biomarkers.

"In terms of staging biomarkers, first we see amyloid, then tau, and finally neurodegeneration or brain atrophy," Apostolova said. "Once we have the ability to do all three scans in the clinic, we will be able to better stage the disease and better counsel patients on their prognosis."

There are currently three tracers approved for amyloid imaging, but as the field turns its interest to tau, new agents that can assess levels of the protein in the brain in vivo are being developed.

For their study, Ances and colleagues studied 59 patients who were either cognitively normal or had Alzheimer's disease. Their mean age was 74 and 64% were men.

All patients had clinical assessments of cognitive impairment, tau imaging, amyloid imaging, and many also had cerebrospinal fluid (CSF) assessment of beta-amyloid, total tau, and phosphorylated tau.

They found that the standardized uptake value ratio (SUVR) used to measure tau in both the hippocampus and cortical regions known to be affected in Alzheimer's disease distinguished normal patients from those with the disease (AUC 0.89 to 0.98).

"This finding is consistent with other neuropathologic studies suggesting that tau burden is closely correlated with disease progression," they wrote.

Tau imaging may have utility in staging Alzheimer's disease, they wrote. Cerebrospinal fluid (CSF) tau levels may indicate disease in the preclinical stage, and volume MRI is a better marker of clinical disease -- but tau in the Alzheimer's cortical signature regions was elevated in both the preclinical and clinical stages, the researchers said.

Thus, tau imaging may detect a wider range of Alzheimer's neurodegeneration than CSF tau or volumetric MRI, they wrote.

The researchers also tried to get a better idea of how tau and amyloid interact in Alzheimer's pathology.

They found that without amyloid, there was no association between hippocampal tau and volume, which supports the view that "without amyloid, age-related hippocampal tauopathy may be insufficient for the neurodegenerative process that leads to Alzheimer's."

On the other hand, there was a strong relationship between tauopathy and hippocampal volume when patients were amyloid-positive -- suggesting an "intriguing hypothesis in which amyloid transforms age-related hippocampal tau to a more toxic species that damages neurons and synapses," they wrote.

They also found the cortical tau was elevated in the presence of amyloid. Taken together, the results support the hypothesis that amyloid "acts as an initiator in a pathogenic cascade that triggers the spread of tauopathy into the neocortex, which in turn leads to cortical neurodegeneration," they wrote.

"In the hippocampus, amyloid likely transforms pre-existing tauopathy to a more toxic species that results in neuronal injury," they wrote. "In the cerebral cortex, amyloid may intensify the spread of tauopathy, which in turn leads to neuronal loss that follows a topography that is similar to the observed spread of neurofibrillary tangles at autopsy."

Apostolova agreed that a positive amyloid scan alone "does not relate to the cognitive state of the patient. Amyloid is not enough to induce atrophy. Once tau is abnormal, only then do we see the neurodegeneration and eventually the cognitive changes."

It also shows that "amyloid makes tau much more toxic to the brain," she said. "Somehow amyloid unlocks that deposition of tau from just in the medial temporal lobe to other areas of the brain."

In an accompanying editorial, William Jagust, MD, of the University of California Berkeley, cautioned that tau imaging is still in early stages of development, but noted that the results are "consistent with indications from neuropathologic studies that have demonstrated stronger associations between tau and cognition than between amyloid and cognition."

"Growing evidence thus suggests that tau and amyloid work together in a particularly malignant way to drive neurodegeneration," he wrote.

The authors disclosed financial relationships with IB International, Roche, AbbVie, Novartis, DiamiR, Eli Lilly, GE Healthcare, and Siemens Healthcare.

Jagust disclosed financial relationships with Genentech, Banner Alzheimer's Institute, Bioclinica, and Novartis.

Source: http://bit.ly/2bliEhT