Lower Motor Neuron Pathology Links ALS and FTLD

Researchers continue to be puzzled by the dual manifestation of TDP-43 proteinopathies as amyotrophic lateral sclerosis, frontotemporal lobar degeneration, or even both. The latest study may help them by confirming that many people with FTLD indeed have TDP-43 pathology in both the brain and spinal cord. In the December 30 JAMA Neurology online, researchers from Nagoya University in Japan describe a series of 29 autopsy cases comprising pure FTLD and mixed FTLD-ALS. They observed TDP-43 inclusions in the spinal cord of all but one case, even when the person’s symptoms during life pointed only to FTLD. “A pathological continuity between FTLD and ALS is supported at the level of the lower motor neurons,” conclude the scientists, led by first author Yuichi Riku and senior author Gen Sobue.

Clinical FTLD can fill the brain with deposits of either tau (FTLD-tau) or TDP-43 (FTLD-TDP). Experts who spoke with Alzforum saw this paper as replicating an FTLD-ALS relationship that many similar studies had already identified (Mackenzie and Feldman, 2005; Geser et al., 2009, reviewed in Neumann, 2013). The current work adds extensive observation of lower motor neurons, Sobue and Riku wrote in an email to Alzforum. “While many investigators have examined brain and spinal-cord tissue with TDP-43 in cases and small series, this is the largest systematic study of TDP-43 staining in brain and spinal-cord tissue among sporadic FTLD-ALS patients,” agreed Bradley Boeve of the Mayo Clinic in Rochester, Minnesota, who was not involved in the study, in an email to Alzforum.

The study authors examined tissues from people who died between 1988 and 2012, apparently from sporadic FTLD. They picked out those who had FTLD symptoms and had donated spinal cord, ending up with nine people whose clinical diagnosis was FTLD alone, eight who presented with FTLD first but later exhibited ALS symptoms, and 12 who started out with ALS but progressed to FTLD as well.

Among the latter group, all 12 had neuron loss and TDP-43 inclusions in the spinal cord. In the eight people who had FTLD first, then ALS also, the pathology was similar but less severe. Of the nine people who clinically had only FTLD, eight exhibited at least some TDP-43 inclusions and neuron loss in the spinal cord. These results support a continuum between ALS and FTLD, the authors conclude. “I think it is a fairly sound result,” said Ian Mackenzie of the University of British Columbia, Vancouver, Canada, who was not involved in the study.

The Japanese authors divided their FTLD cases into three subtypes, as originally defined by Mackenzie and others (Mackenzie et al., 2011). Type A and C FTLD-TDP pathologies occur mainly in layer 2 of the cortex, while type B pathology covers the entire cortex. Mackenzie was intrigued to see that while the pure FTLD cases were all type A or C, the mixed FTLD-ALS cases in the study were all type B. That suggests to him that there may be a continuum between ALS and FTLD type B, but that types A and C fall outside this continuum. These patients might never develop ALS symptoms, despite the TDP-43 pathology in their lower motor neurons, he speculated. “There are still boundaries that do not appear to get crossed.”

Riku and Sobue told Alzforum they had observed one FTLD type A case with ALS, outside the current data set. They were unsure why lower motor neuron pathology was most severe in type B cases.

TDP-43 Proteinopathy Puzzles

TDP-43 clearly connects ALS and FTLD, but “The whys and hows are not adequately understood,” Boeve said. Does TDP-43 cause the pathology, or does it simply represent a marker for neurons in trouble? “That is still a bit of a question mark,” Mackenzie said. When TDP-43 proteinopathy was discovered (see Oct 2006 news story) and TDP-43 mutations were linked to ALS (see Feb 2008 news story), the natural conclusion was that TDP-43 problems caused disease. But as time went on, further studies contradicted this simple model. For example, mutations in progranulin cause FTLD-TDP, and researchers agree the primary cause is progranulin haploinsufficiency. The TDP-43 pathology must be secondary in those cases, Mackenzie said.

Some evidence also suggests that TDP-43 pathology occurs as a secondary event in ALS and FTLD due to C9ORF72 expansions, since sometimes these cases have remarkably low levels of TDP-43 inclusions (Gijselinck et al., 2012). Mackenzie told Alzforum that he and colleagues in Oxford, U.K., had recently observed a case in which a C9ORF72 expansion carrier died of heart disease when he already exhibited FTLD symptoms, but no TDP-43 pathology had yet appeared in his brain. Therefore, the C9ORF72 must cause problems before TDP-43 gets involved. “Maybe [TDP-43 proteinopathy] is just a common sort of stress response of neurons,” Mackenzie suggested. He said he feels less certain now than he did in the the early years of TDP-43 research that the protein directly triggers ALS and FTLD in all cases.

John Trojanowski of the University of Pennsylvania in Philadelphia brought up a similar conundrum, pointing out that mutations in eight different genes result in TDP-43 proteinopathy. These include TDP-43 itself, C9ORF72, progranulin, VCP (valosin-containing protein, Neumann et al., 2007), ubiquilin 2 (Williams et al., 2012), angiogenin (Kirby et al., 2013), optineurin (Kamada et al., 2013), and NIPA1 (non-imprinted in Prader-Willi/Angelman syndrome, Martinez-Lage et al., 2012), which causes TDP-43 proteinopathy in hereditary spastic paraplegia. “It’s amazing that abnormalities in eight different genes result in TDP-43 pathology,” Trojanowski wrote to Alzforum. “It will be an interesting story when we learn how this happens.” Similarly, tauopathies like FTLD-tau also result from mutations in different genes.—Amber Dance

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