While chatting to a friend, I noticed a rolled up magazine in his bag. It caught my eye because it was open on a page with Sudoku on it.
“Oh hey! I didn’t know you enjoyed Sudoku. When did that happen?” I queried amusedly. You see my friend isn’t usually a puzzle type of person. Sports, yes. Fad diets, yes. Crossfit, yes. Puzzles, no.
My friend pulled out the magazine looking as almost surprised as I did.
“Yeah, I’m not usually into that sort of thing but my grandmother has late stage Alzheimer’s and I’m worried it’s in my genes. I’ve heard it’s good to keep your brain active and that Sudoku works wonders. Figured it couldn’t hurt!”
That’s a quarter of a trillion dollars…
Dementias include Huntington’s, Parkinson’s, post-stroke (vascular) dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies, amyotrophic lateral sclerosis (ALS) and others.
When you factor in other neurodegenerative diseases like multiple sclerosis (MS), motor neuron disease, prion disease, spinocerebellar ataxia, spinal muscular atrophy, not to mention more rare disorders like Tay-Sachs disease, you can imagine the impact in terms of the massive number of people affected and the extraordinary impact this has disease burden has on our lives.
So why, why, why when the incentives are so astronomically high haven’t we cured neurodegenerative disease?
For that matter, why can’t we just prevent in it the first place?
There are some harsh realities to be faced here but also some hope for the future. Let’s take a look.
Problem #1: Diagnosis…and Misdiagnosis
Here in the US, folks’ point of medical care is usually their primary care physician. Neurodegenerative disorders can be very hard to diagnose and when you add to the mix that it’s a garden variety physician who probably only sees you at max once a year, the odds of making a correct and prompt diagnosis are unsatisfactory to say the least. Even if you are seen by a specialist, many neurodegenerative diseases have overlapping symptomatology so misdiagnosis is unfortunately far too common as well. Let’s look at MS with its hallmark symptoms of numbness, tingling, pain, fatigue, and heat sensitivity. These also sound like many other possible diagnoses from Conversion and psychogenic disorders to vasculitis to stroke to lupus to migraines.
Now, which is a primary care doctor more likely to presume you have: chronic migraines or MS?
To diagnose MS, you need a detailed family history (which relies on high accuracy from patients), a neurological exam, MRI, perhaps a lumbar puncture and the elimination of any other possible similar problem. To top it, you may not even have these hallmark symptoms.
Right now we need biomarkers for many neurodegenerative diseases and we just don’t have them. Genetic testing can be very helpful when there is a strong family history, as is the case for Huntington’s Disease, but we don’t have a quantitative, accurate and non-subjective way to diagnose neurodegenerative disorders at this point. The path towards diagnosis is long and murky.
Problem #2: Clinical Research takes an Especially Long Time
With very long-term illnesses like Alzheimer’s it will take many years and many patients to know for sure it making a significant difference.
In addition, imagine how hard it is to recruit patients who are either drug-naive or who are willing to go off their medications for the study to a drug that in all likelihood won’t work.
Even just to get approval to run one of these trials is challenging.
Don’t get me started on how long it takes to even get a drug from an idea to a possible treatment in a study…
Problem #3: We Just Don’t Know Enough Yet
We really don’t know enough about these disorders to begin with. We know some of the genetic factors that can play a role and there are also environmental risk factors but in the end of the day we don’t know what triggers many of these disorders: could be a pathogen, gene(s), toxin, we just don’t know yet.
For example, for years, researchers struggled to get drugs through the blood-brain barrier (BBB). That tissue is there for a reason: to keep toxins out and boy, howdy are the drugs we’re using toxic. We thought if we could get it through we were golden and so we shook our fists at the BBB in frustration assuming it was nothing more than a barrier to isolate the brain. Recent research has shown that actually the BBB may play a significant role in disease outcome and progression.
Trying to fight an enemy you only have partial data on does not give you the odds you want to win the war.
Problem #4: Poor in vivo and in vitro models
This one speaks for itself. A disorder as intricate and complex as, for example, MS requires a reliable model to experiments on (other than people!). Our current in vivo models like the EAE mouse are just not good enough. Same goes for our in vitro models. For example, immortalized cell lines that express heterologous genes are used to screen drug compounds. While models like these help us gain some hints into what may be happening in the body, they’re limited by their own simplicity. They’re an approximation of the real deal, everything from the cell-cell interactions to the environment the cell is in.
A More Hopeful Future
We are making progress however!
- New molecular diagnostics to diagnose Alzheimer’s, MS and ALS are in progress.
- New evidence for the role of the gut in Parkinson’s.
- DNA repair as a shared mechanism in neurodegeneration.
- New evidence of prion protein ‘seeds’.
- Linking an ALS gene to autoimmunity.
- The role of microglia genes in Alzheimer’s.
- New understanding of cognitive aging.
- The part played by actin proteins in ALS.
- Understanding the role of tau proteins in neurodegeneration.
- Improvements in in vitro techniques and models such as induced pluripotent stem (iPS) cell-derived human cells and patient-derived xenografts.
To name but a few recent advances!
We have a long way to go, but we’ve come a long way.
Article by Olwen Reina. Contact Olwen at firstname.lastname@example.org.
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