TDP-43 Routes Mapped in Alzheimer’s, Frontotemporal Dementia

Pathological TDP-43 appears to follow a set route through the nervous system, and what that route is depends on the disease at hand. Two new papers in Acta Neuropathologica add TDP-43 itineraries for Alzheimer’s disease and frontotemporal lobar degeneration to a previously published staging scheme for amyotrophic lateral sclerosis (see Nov 2013 news story). While the starting points and paths taken differ, the disease-specific routes suggest that TDP-43 travels from neuron to neuron along axonal highways. The stages should also provide convenient shorthand for pathologists to describe a patient’s pathological burden.

The TDP-43 stages fit with the ongoing theme in neurodegeneration research that these diseases are progressive not only over time, but also in space, as pathological proteins spread throughout the nervous system, according to John Ravits of the University of California in San Diego, who was not involved in the current studies. Researchers have defined stages of Aβ, tau, and α-synuclein proteinopathy by examining autopsy tissue from people who died at various points in the progression of their disease (Braak et al., 2006; Braak and Braak, 1991; Braak et al., 2003). Rather than flowing freely through the nervous system, these proteins appear to follow defined neuroanatomical pathways (see Jun 2009 news story; Apr 2012 news story).

The FTLD study, published online January 10, comes from the same group that performed the ALS staging study. Senior authors Heiko Braak of the University of Ulm, Germany, and John Trojanowski of the University of Pennsylvania in Philadelphia led the project. Joint first authors Johannes Brettschneider and Kelly Del Tredici of Ulm and David Irwin of Pennsylvania examined 39 cases of behavioral variant frontotemporal dementia to define a pattern of sequential pathology. In the lowest-burden cases, TDP-43 inclusions occurred in the basal forebrain (see image below). In the next stage, the proteinopathy progressed to the prefrontal area. In the third pattern defined by the group, TDP-43 pathology also occurred in the brainstem, motor cortex, and spinal cord grey matter. In the most severe cases, it hit occipital areas, too.

Overall, Trojanowski summed up, the FTLD pathology progressed from the front of the brain to the back. This contrasted with the ALS staging system, which began in the motor cortex at the brain’s apex and moved downward and forward from there. “The spreading mechanisms could be very similar, but the early focus of pathology seems to be different [between ALS and FTLD],” Brettschneider said. Trojanowski added, “This reflects the different clinical manifestations. Why this happens is mysterious.” The researchers selected relatively homogeneous cases of clinically pure FTLD or pure ALS to obtain clear staging; cases with a mixture of symptoms would likely show different pathological pathways, Trojanowski said.

Looking to TDP-43’s spread in Alzheimer’s, senior author Dennis Dickson of the Mayo Clinic in Jacksonville, Florida, and colleagues report their findings in a study published online November 16, 2013. First author Keith Josephs of the Clinic’s branch in Rochester, Minnesota, identified TDP-43 pathology in 195 out of 342 autopsy AD cases—a “staggering” proportion that suggests TDP-43 inclusions appear in more than half of Alzheimer’s patients, he said. The authors defined a five-stage progression of TDP-43 inclusion pathology, starting with the amygdala, then moving to the entorhinal cortex and subiculum, followed by the dentate gyrus and occipitotemporal cortex, and thereafter the inferior temporal cortex. In the final stage, the middle frontal cortex and basal ganglia were also affected.

The pathology moves from the amygdala to memory-controlling areas to the cortex, Josephs summarized. This pathway differs from the routes taken by Aβ and tau. Notably, amyloid does not arise in the amygdala. Josephs was uncertain why TDP-43 pathology began there, but noted the amygdala often contains proteinopathy in neurodegenerative disease.

The brain areas examined by the two research groups were not entirely identical, and some overlapping locales could have been missed. Like tau, TDP-43 occurs in different places in different conditions.

How can the same misfolded protein appear in AD, FTLD, and ALS? “I ask myself this question all the time, but I cannot answer it,” Brettschneider said. He speculated that perhaps pathological TDP-43 occurs in different “strains,” as has been shown for alpha-synuclein and prions, and each strain occurs in a different disease (see Jul 2013 news story; Colby and Prusiner, 2011).

When pathological TDP-43 does occur, does it cause the disease, or simply mark degenerating neurons? “I personally think it does both,” Josephs said. TDP-43 may indicate general neurodegeneration, but must also drive the process in cases where it is the only proteinopathy present, he said (see also Jan 2014 news story).

Though these studies point to axonal routes for the spread of TDP-43 from region to region, the evidence provided for this by autopsy tissue is at best indirect. Another possibility, Ravits suggested, would be that TDP-43 diffuses indiscriminately across the brain, but only certain neural types are susceptible to the traveling pathology. Trojanowski said studies in mouse and cell culture models are up next to clinch the mechanism of TDP-43 transfer.

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