The brain bank for neurodegenerative disorders at Mayo Clinic in Jacksonville, Florida houses the world’s largest collection of brains from people with PSP and with CBD.  It currently makes available to researchers world-wide about 9,000 brains overall, including about 3,000 with Alzheimer’s disease, 2,000 with Parkinson’s disease or Lewy body dementia, and nearly 3,000 with the neurofibrillary tangle disorders listed below. The table also shows the number of each along with some random comments.

First, an FYI: Don’t assume that the relative proportions of these disorders in the brain bank reflect their relative prevalence in the population. Brain banks disproportionately attract unusual conditions where the diagnosis during life was unclear and the family is seeking an accurate, expert final diagnosis as much as they’re making a charitable gift to research.

PSP	1,762	CurePSP encourages brain donations to this brain bank and subsidizes the cost of brain removal and shipping for families who cannot afford those costs.
Corticobasal degeneration	358	It can be very difficult to distinguish CBD from PSP during life.  About half of people with corticobasal syndrome during life turn out to have CBD at autopsy.
Neurofibrillary tangle dementia	267	This is an umbrella term for dementing illnesses with NFTs other than Alzheimer’s disease.
Frontotemporal dementia with a mutation in the MAPT (tau) gene	86	A rare, hereditary form of frontotemporal dementia.  Depending on the type and location of the mutation within the MAPT gene, it can closely mimic PSP both during life and at autopsy.
Chronic traumatic encephalopathy	78	Caused by repeated blows to the head in susceptible individuals. The location of its neurofibrillary tangles is very different from that of any of these others or Alzheimer’s disease.
Pick’s disease	77	This is a non-hereditary form of frontotemporal dementia, with more motor and language deficits than most other forms of FTD.
Globular glial tauopathy	46	During life, this produces speech apraxia, parkinsonism, behavioral changes, eye movement changes. It also has lower motor neuron changes similar to those in ALS.
Total:	2,674

These are impressive numbers and you might ask why CurePSP is still encouraging families to donate their loved one’s brain.  In other words, why do we need more?  It comes down to statistics and genetics.  Stay with me here and — spoiler alert — some details in the next paragraph may be unpleasant to think about:

Each donated brain is sliced into right and left halves and then into one-centimeter-thick slabs.  One half is put into a preservative solution for two weeks before it’s firm enough to be sampled for examination under a microscope.  That establishes the diagnosis, and the pathologist at the brain bank sends a detailed report to the family and local physician if the family so requests.  The other half is frozen for use in research on the chemical components, including proteins, DNA and RNA. 

About 15 years ago, CurePSP funded a project using DNA extracted from the brain samples then available from the Mayo brain bank along with some from other, much smaller brain banks.  The research group created for that was called the PSP Genetics Consortium.  Its 2011 publication reported that variants in five genes were more frequent in PSP than in controls without PSP.  One of those variants confirmed the previously-discovered association of the “H1 haplotype” with PSP.

(I’ll digress for a bit here. The H1 haplotype is a span of chromosome 17 that encompassing the MAPT gene and about a dozen others. The variantisn’t a simple substitution of one nucleotide (as each “letter” in the genetic code is called) for another. Rather, it’s an “inversion,” a long string of genes occurring in reverse order on its chromosome.  The H1 haplotype actually is present on both copies of chromosome 17 in about 60% of European-derived populations but in 88% of those with PSP — a statistically significant difference but far from a full explanation. End of digression.)

That 2011 analysis found another variant at a specific locus inside the MAPT gene plus three others on different chromosomes, each of which performs functions consistent with what’s known about how PSP works. They’re called EIF2AK3, MOBP and STX6.

Two other genes called SLCO1A2 and DUSP10 have since been found to increase PSP risk and one other, TRIM11, has been found to affect onset age of PSP, but not the chance of developing the disease in the first place. And that’s it so far, other than a bunch of mutations in MAPT associated with very rare, strongly-inherited, familial forms of frontotemporal dementia closely mimicking PSP.

The conundrum is that even adding the influence of all of these known gene variants together can’t explain the magnitude of population’s prevalence of PSP, small though it is.  One possibility is some strong, unidentified environmental factor.  Another is that many more PSP-risk-conferring genes, each with only a tiny statistical effect, await discovery.  They wouldn’t have appeared in the 2011 analysis for lack of enough brain samples to reveal their weak statistical “signals.” That analysis relied on comparing the frequencies of gene variants between the brains from people with PSP to a group without PSP. Any variant with a difference greater than what might be expected by chance is considered a genetic “hit.”

The Genetics Consortium tried solving that problem by doing whole-exome and whole-genome sequencing in the original set of brain samples plus a few hundred others that had accrued since.  Those studies are not yet published, but my information is that they have produced at most one more hit, called TREM2, which was already known to be a risk gene for Alzheimer’s disease.

So, the solution is more samples from more donated brains with PSP.  Barring some breakthrough in genetic technology, that’s the only way we’ll ever have enough samples to compare with controls to tease out more hits — gene variants each contributing only a tiny degree of risk.

Why bother, you say?  The main reason is that identifying a risk gene may point to a specific protein or biochemical pathway (a set of closely related chemical reactions in the cell) that, when impaired for any reason, results in the disease.  Then, researchers have a “drug target” on which to focus their search for ways to improve the performance of that chemical or pathway. 

Another reason to bother with the genetics of PSP is that if we identify enough risk genes, we can create a diagnostic test panel based on a “polygenic risk score.”  That’s where DNA from someone suspected of having PSP would be tested for all of the gene variants known to contribute PSP risk.  If enough of them are present (or present in a specified combination), the diagnosis is made* and the person can enter a clinical trial at an early stage or can receive a disease-slowing drug that might be available by then.

So, if you have PSP, I hope we find a cure during your lifetime.  But if we don’t, please consider making (non-binding) arrangements to donate your brain to a research-oriented brain bank like the one at the Mayo Clinic in Jacksonville.  More information is available here.

* It might seem that having a set of genetic variants associated with PSP would be pretty good proof of the diagnosis. But it turns out that a majority of people with mild brain cell damage of PSP at autopsy never actually had outward signs of PSP, even into their 80s. During life, such a person would have a positive genetic diagnosis but their outward neurological symptoms might be caused by something else. More on this in a future post.