ALS CLASSROOM: ALS and the BrainALS’s brain effects are real. Here's what we know that we didn’t a decade ago.
It’s not hard to see why, less than a decade ago, physicians may not have picked up on cognitive problems that many ALS patients experience. For a person to find decision-making troublesome or to struggle for the right word or to seem a little withdrawn — all while having indeniable difficulties in swallowing, breathing and moving — has just seemed a natural response to stress. A smaller number of patients, however, have obvious difficulty in thinking or lose their inhibitions or perhaps bubble with euphoria — something easier to spot and something that’s long been seen as a variation of ALS that can develop, and not the classic disease. But, until recently, brain involvement of any sort in ALS hasn’t been much discussed, other than by clinicians among themselves or, of course, with the patients and families who experience it. The science has also been relatively sparse. Compared with the extent of neuromuscular research in ALS, studies on its brain-based aspects are especially few.* Work on the more serious condition, known as frontotemporal dementia (FTD), has, for example, largely been confined to describing symptoms, or to mapping areas of brain injury and seeing how they differ from other diseases. So FTD and some other dementias now fall in a larger category — frontotemporal lobar degeneration (FTLD) — that’s based on pathology.** Patients with FTLD all show gradual, continuous tissue loss in frontal and anterior temporal lobes of the brain. But recently there’s come a sea change – and a quick one, as these things
go — in understanding ALS and the brain. Two waves of discovery are swamping old ideas as they attract even more research and, with it, bring a cautious optimism that we’re on a surer track to therapy. Much More Common First came the realization that brain involvement is more common in ALS than suspected. That news surfaced around 2002, when neurologist Catherine Lomen-Hoerth (she now directs the ALS Center at the U. of California, San Francisco) and colleagues extensively examined patients diagnosed with sporadic FTLD. These were people not diagnosed with any motor disease. But the research team found that wasn’t the case: 14 percent had early ALS. A further 36 percent possibly had it.
Since then, other study confirms what many clinicians had begun to suspect: roughly half of ALS patients experience mild cognitive or behavioral problems and perhaps 15 percent of those have some form of frontotemporal dementia. A second research wave — one closer to cause — broke in 2006 and is still ongoing. It’s part of work that unites the neurodegenerative illnesses like Parkinson’s, Alzheimer’s and ALS as proteinopathies — diseases somehow encouraged by having flawed genes that, in turn, code for characteristic misfolded proteins. Finding the specific proteins and their respective genes in neurodegenerative illnesses has been an intense research focus. In Alzheimer’s and Parkinson’s the science is farther along than in rarer ALS. For them, likely culprit proteins have been known for a decade or more. ALS, however, is catching up. A New SuspectIn 2006, John Trojanowski and Virginia Lee and their team at the University of Pennsylvania announced evidence that the misfolded TDP-43 molecule was not only the major flawed protein in sporadic and many familial ALS patients but that the same misfolded TDP-43 was also key in ALS-associated frontotemporal dementia.*** Since then, a host of studies by that group and others have shaped and strengthened the idea that scientists are coming to accept: The diseases are all of a piece. Most patients with 1) classic ALS or 2) those who have ALS with frontotemporal dementia or 3) ALS with milder symptoms of brain effects are likely part of a spectrum of disease that also includes 4) people with the most common, pure frontotemporal dementia — one that comes without apparent neuromuscular illness. In all, flawed TDP-43 is a common theme. Clumps, Fibers and DotsThe natural next question is why disease would center on the spinal cord in some patients and on the brain’s frontal and temporal cortex in others. Answers are by no means at hand, but now a logical foundation’s being set for them. It begins by using antibody-based tracers for TDP-43. With them, researchers are highlighting exact locations of the flawed protein in central nervous system tissue — which cell types house it, whether it’s inside cell nuclei or cell cytoplasm, where it exists in the spinal cord and in the brain. Microscopically, cellular deposits containing TDP-43 take on a variety of shapes, from dark-staining clumps (inclusions) to fine fibers to granular dots. Why that’s the case isn’t clear. What is clearer, however, is that, generally, the location of the pathology and symptoms match up. Misfolded TDP-43 confined largely in the outermost cerebral cortex, for example, is more typical in patients with dementia but not motor neuron disease. And the brains of patients with both ALS and cognitive effects are more likely to have heavy pathology both in the outer cortex and deeper in the brain’s movement centers as well as in the spinal cord. Now work is underway to draw therapy closer. Packard scientists have quickly seen the need to create a variety of the TDP-43 model animals and, for the first time, they and colleagues at sister academic institutions are creating human ALS patient stem cell-derived cultures that will best show precisely how the molecule plays out in nervous system cells. Paul Taylor, a Packard researcher, has already shown that TDP-43 itself is a toxic agent, a key first step. And the U-Penn team, Packard and others continue intense research into TDP-43’s mechanism. “The possibility that a common mechanism could underlie all these forms of disease is driving the search for a keystone target for therapy,” says Lomen-Hoerth, “and has brought new excitement to the field.” In the MeantimeUntil a therapy arrives, there has to be some comfort, though it’s small, in knowing that most cognitive and behavioral changes that may appear in ALS patients have a biological basis. Currently, those and more serious mental effects like dementia are best approached using the same behavioral tactics and, in some cases, the medications that temporarily improve function and quality of life for patients with Alzheimer’s disease. Lomen-Hoerth cautions that some Alzheimer’s medications make frontotemporal dementia worse, so consulting specialist clinicians is important. Helpful Links:
http://www.alsa.org/files/pdf/fyi/Cognitive_Impairment_Prof.pdf
http://www.alsa.org/research/article.cfm?id=825
http://www.ncbi.nlm.nih.gov/pubmed/20102519 | 
