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

Comments

  1. While many investigators have examined brain and spinal cord tissue with TDP in cases and small series, this is one of the largest systematic studies of TDP staining in brain and spinal-cord tissue among sporadic FTLD-ALS spectrum patients regardless of antemortem clinical syndrome (FTLD without ALS, FTLD-ALS, or ALS-FTLD). As would likely be expected by many investigators in this field, TDP pathology was evident across the upper- and lower-motor-neuron networks regardless of antemortem syndrome.

    These findings further support the view that the clinical and neuropathologic features of FTLD-ALS represents a spectrum with a likely similar pathophysiology, but the precise mechanisms involved in TDP-associated neurodegeneration remains unclear.

    TDP-43 ties together some of the genetically mediated FTLD and/or ALS disorders (e.g., progranulin, C9ORF72, and many others) as well as many sporadic FTD and/or ALS cases, but the whys and hows are not adequately understood.

    In my mind, these findings also underscore several important concepts relating to clinicopathologic correlations, more specifically: 1) antemortem detection of clinical deficits, 2) thresholds of clinical expression of neurodegeneration, and 3) protein deposition-neurodegeneration correlations. These concepts help to cloud the interpretation (but do not detract from the importance and significance) of any clinicopathologic study in neurodegenerative disease.

    1) Antemortem detection of clinical deficits: As patients evolve into the terminal phase of FTLD-ALS, they are typically not evaluated as frequently and perhaps also not as diligently, and therefore a patient with behavioral variant FTD (bvFTD) may develop ALS late in the course, or an ALS patient may develop bvFTD features late in life, and these may go undetected. If one assesses for bvFTD features in those with ALS, the features are often present even if they are not obvious or problematic (as demonstrated by Catherine Lomen-Hoerth and colleagues, and others). Furthermore, examining for bvFTD features becomes increasingly more difficult in progressively severe ALS patients, and vice versa. Finally, electromyography (EMG) may reveal electrophysiologic changes of lower-motor-neuron dysfunction that are not apparent on purely clinical grounds (this was also demonstrated by Lomen-Hoerth et al., and many others). Thus, some patients diagnosed with bvFTD may have ALS during life but not appreciated (and thus their final clinical diagnosis is bvFTD), and vice versa (and thus their final clinical diagnosis is ALS), thereby potentially altering the interpretation of clinicopathologic correlations in this paper and many other papers in neurodegenerative diseases.

    2) The thresholds of clinical expression of neurodegeneration: What degree of neuronal degeneration in frontotemporal neural networks is required to manifest as bvFTD? What degree of degeneration in upper motor neurons is required to manifest as the upper-motor-neuron dysfunction component of ALS? And what degree of degeneration in the lower motor neurons in cranial nuclei and spinal cord is necessary to manifest as the lower-motor-neuron dysfunction component of ALS? Is there patient-to-patient variability? Probably. These questions are not adequately answered, limiting the interpretation of clinical expression of neurodegeneration.

    3) Protein deposition-neurodegeneration correlations: Clinical deficits correlate with the corresponding neuronal dysfunction, but not necessarily with abnormal protein deposition in neurons and/or glia. In other words, the presence of TDP43 in any neuron may or may not be associated with functional impairment of that neuron; this same concept applies to the presence of other presumably abnormal protein accumulations (e.g., α-synuclein) in neurons. Therefore, finding TDP deposition in lower motor neurons in a patient with bvFTD throughout life may suggest a continuum of TDP deposition along the motor-neuron axis, but whether that patient ever would have exhibited ALS features had he/she lived long enough is not known.

    View all comments by Brad Boeve

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References

News Citations

  1. New Ubiquitinated Inclusion Body Protein Identified
  2. Gene Mutations Place TDP-43 on Front Burner of ALS Research

Paper Citations

  1. Mackenzie IR, Feldman HH. Ubiquitin immunohistochemistry suggests classic motor neuron disease, motor neuron disease with dementia, and frontotemporal dementia of the motor neuron disease type represent a clinicopathologic spectrum. J Neuropathol Exp Neurol. 2005 Aug;64(8):730-9. PubMed.
  2. Geser F, Martinez-Lage M, Robinson J, Uryu K, Neumann M, Brandmeir NJ, Xie SX, Kwong LK, Elman L, McCluskey L, Clark CM, Malunda J, Miller BL, Zimmerman EA, Qian J, Van Deerlin V, Grossman M, Lee VM, Trojanowski JQ. Clinical and pathological continuum of multisystem TDP-43 proteinopathies. Arch Neurol. 2009 Feb;66(2):180-9. PubMed.
  3. Neumann M. Frontotemporal lobar degeneration and amyotrophic lateral sclerosis: Molecular similarities and differences. Rev Neurol (Paris). 2013 Oct;169(10):793-8. PubMed.
  4. Mackenzie IR, Neumann M, Baborie A, Sampathu DM, Du Plessis D, Jaros E, Perry RH, Trojanowski JQ, Mann DM, Lee VM. A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol. 2011 Jul;122(1):111-3. Epub 2011 Jun 5 PubMed.
  5. Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G, Janssens J, Bettens K, Van Cauwenberghe C, Pereson S, Engelborghs S, Sieben A, De Jonghe P, Vandenberghe R, Santens P, De Bleecker J, Maes G, Bäumer V, Dillen L, Joris G, Cuijt I, Corsmit E, Elinck E, Van Dongen J, Vermeulen S, Van den Broeck M, Vaerenberg C, Mattheijssens M, Peeters K, Robberecht W, Cras P, Martin JJ, De Deyn PP, Cruts M, Van Broeckhoven C. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol. 2012 Jan;11(1):54-65. PubMed.
  6. Neumann M, Mackenzie IR, Cairns NJ, Boyer PJ, Markesbery WR, Smith CD, Taylor JP, Kretzschmar HA, Kimonis VE, Forman MS. TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations. J Neuropathol Exp Neurol. 2007 Feb;66(2):152-7. PubMed.
  7. Murray ME, Dejesus-Hernandez M, Rutherford NJ, Baker M, Duara R, Graff-Radford NR, Wszolek ZK, Ferman TJ, Josephs KA, Boylan KB, Rademakers R, Dickson DW. Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72. Acta Neuropathol. 2011 Dec;122(6):673-90. PubMed.
  8. Kirby J, Highley JR, Cox L, Goodall EF, Hewitt C, Hartley JA, Hollinger HC, Fox M, Ince PG, McDermott CJ, Shaw PJ. Lack of unique neuropathology in amyotrophic lateral sclerosis associated with p.K54E angiogenin (ANG) mutation. Neuropathol Appl Neurobiol. 2012 Dec 10; PubMed.
  9. Kamada M, Izumi Y, Ayaki T, Nakamura M, Kagawa S, Kudo E, Sako W, Maruyama H, Nishida Y, Kawakami H, Ito H, Kaji R. Clinicopathologic features of autosomal recessive amyotrophic lateral sclerosis associated with optineurin mutation. Neuropathology. 2014 Feb;34(1):64-70. Epub 2013 Jul 29 PubMed.
  10. Martinez-Lage M, Molina-Porcel L, Falcone D, McCluskey L, Lee VM, Van Deerlin VM, Trojanowski JQ. TDP-43 pathology in a case of hereditary spastic paraplegia with a NIPA1/SPG6 mutation. Acta Neuropathol. 2012 Aug;124(2):285-91. PubMed.

Further Reading

Papers

  1. Al-Sarraj S, King A, Troakes C, Smith B, Maekawa S, Bodi I, Rogelj B, Al-Chalabi A, Hortobágyi T, Shaw CE. p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol. 2011 Dec;122(6):691-702. PubMed.
  2. Brettschneider J, Libon DJ, Toledo JB, Xie SX, McCluskey L, Elman L, Geser F, Lee VM, Grossman M, Trojanowski JQ. Microglial activation and TDP-43 pathology correlate with executive dysfunction in amyotrophic lateral sclerosis. Acta Neuropathol. 2012 Mar;123(3):395-407. PubMed.
  3. Geser F, Stein B, Partain M, Elman LB, McCluskey LF, Xie SX, Van Deerlin VM, Kwong LK, Lee VM, Trojanowski JQ. Motor neuron disease clinically limited to the lower motor neuron is a diffuse TDP-43 proteinopathy. Acta Neuropathol. 2011 Apr;121(4):509-17. PubMed.
  4. Kwong LK, Neumann M, Sampathu DM, Lee VM, Trojanowski JQ. TDP-43 proteinopathy: the neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease. Acta Neuropathol. 2007 Jul;114(1):63-70. PubMed.
  5. Mackenzie IR. The neuropathology of FTD associated With ALS. Alzheimer Dis Assoc Disord. 2007 Oct-Dec;21(4):S44-9. PubMed.
  6. Van Langenhove T, van der Zee J, Van Broeckhoven C. The molecular basis of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum. Ann Med. 2012 Dec;44(8):817-28. Epub 2012 Mar 16 PubMed.

Primary Papers

  1. Riku Y, Watanabe H, Yoshida M, Tatsumi S, Mimuro M, Iwasaki Y, Katsuno M, Iguchi Y, Masuda M, Senda J, Ishigaki S, Udagawa T, Sobue G. Lower motor neuron involvement in TAR DNA-binding protein of 43 kDa-related frontotemporal lobar degeneration and amyotrophic lateral sclerosis. JAMA Neurol. 2014 Feb;71(2):172-9. PubMed.

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