Tag Archives: parkinsons-disease

Turning on the data tap at GP2

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A new paper in the journal JAMA Neurology presents a progress report from the Global Parkinson Genetics Program, or “GP2.” That’s a world-wide collaboration to study the genetics not only Parkinson’s disease, but also dementia with Lewy bodies, multiple system atrophy, corticobasal degeneration — and PSP.  Started in 2020, GP2 eventually plans to enroll 250,000 participants at 415 academic centers in 70 countries.  Its funding is mostly from the Sergey Brin Family Foundation to Aligning Science Across Parkinson’s (ASAP), and the complicated nuts and bolts of the project are organized by the Michael J. Fox Foundation. The paper is entitled “Pathology and Genetics in a Global Cohort of Parkinsonian Disorders,” with first author Dr. Lesley Wu and senior author Dr. Huw Morris, both of UCL Queen Square Institute of Neurology in London.

Our knowledge of the genetics of PSP, PD and the other Parkinsonian disorders remains insufficient, and the little we do know is based almost entirely on studies of white, European-derived populations.  The goal of GP2 is to extend our knowledge of the genetics of the Parkinsonian disorders to include non-European-derived populations as well.  Why?  Two reasons:

  • The most obvious justification is to allow all to benefit from tests and treatments arising from genetic knowledge. 
  • Another is to Identify genetic variants associated with the disease in previously under-studied gene pools.  That could identify previously unsuspected brain chemical processes that could in turn point to new treatment targets — not only for members of those ethnic groups or with those gene variants, but for the diseases in general, world-wide.

Examples of the groundbreaking success of this approach in neurodegenerative diseases have been a family in rural Venezuela with a mutation in the huntingtin gene causing Huntington’s disease, and one in rural southern Italy with a mutation in the alpha-synuclein gene causing a form of Parkinson’s disease.  In each case, the gene was not previously known to have any relationship to its respective disease.  In each, the genetic insight has resulted in new scientific understanding, diagnostic tests and experimental neuroprotective treatment for the disease in anyone.  Both examples, however, are based on dominant-acting mutations manifesting mostly in the young or middle-aged, where a familial pattern is obvious.  But in the vast majority of neurodegenerative diseases, any genetic component is more subtle, with each genetic “risk variant” contributing only a smidge to the overall disease likelihood, and familial patterns are often undetectable by laypersons or ordinary medical testing.

One of the first tasks for the GP2 study is to use autopsies to make sure that the people whose DNA samples have been obtained really do have the disease their neurologist has diagnosed. 

The analysis included 3,403 autopsies. Of those individuals:

• 1,171 had been diagnosed during life with PD
• 399 with Parkinson’s disease dementia (PDD)
• 227 with dementia with Lewy bodies (DLB)
• 491 with PSP
• 244 with MSA
• 76 with CBS

Here’s a table comparing the pre-mortem (or “clinical”) diagnoses with autopsy results:  The columns are the clinical diagnoses and the rows are those made at autopsy.  So, for example, of those with corticobasal syndrome diagnosed during life, 16% turned out to have Alzheimer’s disease at autopsy.

Autopsy diagnosisPercentage with Clinical Diagnosis
PDPDDDLBPSPMSACBSControls
Lewy body disease90%96%94%7%17%8%4%
Alzheimer’s1%1%3%0%0%16%1%
PSP3%2%1%88%7%36%0%
MSA3%0%0%2%75%5%0%
CBD0%0%0%1%0%24%0%
Other neuro-degen.2%1%0%2%1%12%2%
No neuro-degen.0%0%1%0%0%0%93%

Footnotes for this table:

  • “Lewy body disease” is the autopsy picture underlying the clinical spectrum that includes Parkinson’s disease, Parkinson’s disease dementia and dementia with Lewy bodies.  Those three conditions are now widely considered to be sub-types of the same disease, just as PSP-Richardson syndrome and PSP-Parkinsonism are sub-types of PSP.
  • For visual simplicity, I’ve rounded all percentages to the nearest integer, so some of the “0%” figures are actually 0.1% to 0.4%.
  • “Other neurodegen.” comprises aging-related tau astrogliopathy, argyrophilic grain disease, chronic traumatic encephalopathy, primary age-related tauopathy, Pick disease, tauopathy not otherwise specified, and vascular pathology.

Take-homes from this table:

  • A clinical diagnosis of PSP is highly accurate, but far from optimal, with 88% confirmed at autopsy.  The next most common autopsy result in such individuals is Lewy body disease, at 7%.
  • Of those with a clinical diagnosis of CBS, only 24% proved to have CBD at autopsy.  A more typical figure from the literature is 40-50%. 
  • Of those with a clinical diagnosis of CBS, 36% proved to have PSP at autopsy.  A more typical figure from the literature is 25%.

The main point of the project, however, is the genetics.  The 20 genes analyzed in this paper were selected because of their known association with the Lewy body diseases.  However, six of them did appear in at least one of the 531 people with PSP who underwent genetic analysis.  They are:

  • The MAPT gene, which encodes the tau protein.  The H1/H1 haplotype (where each of the two copies of chromosome 17 carries the variant) occurred in 83% of people with PSP and in 48-72% of the other groups.  This was first discovered in 1998, so no news there.
  • The LRRK2 (“lark-two”) gene, which encodes an enzyme involved in breakdown of abnormal tau by the lysosomes, showed a variant in 2 people (0.4%) with PSP and in 0.8% with the Lewy body diseases.  This is also no different from previously known statistics.  The lysosomes are one of the cell’s most important mechanisms for disposing of defective, worn-out or excessive proteins such as tau.
  • 29 (16%) of the people with PSP carried one of the known disease-associated variants in the GBA1 gene.  That encodes the enzyme glucocerebrosidase, which like LRRK2, relates to the lysosomes.  This percentage was less than for LBD but did not differ from the other diseases.  Also no surprise, based on previous research.
  • Two results related to ethnicity: 
    • Ashkenazi Jews, regardless of diagnosis, were more likely than all other groups to carry variants in the GBA1 gene.  This has been known since the original description of a GBA1-Parkinson’s relationship in 1996. 
    • South Asians, regardless of genetic results, were more likely to have PSP than other ethnic groups.  This has been informally suspected, but as far as I know, this paper provides the first (admittedly meagre) actual statistics. A deeper dive into the association must now be done:  For example, are neurologists in South Asia better informed when it comes to PSP than neurologists elsewhere?  In the US, where South Asians are a relatively prosperous community with a disproportionate number of physicians, does that group tend have better access to PSP expertise than other ethnicities?  When I know, you’ll know.

  Overall take-homes:

  • This genetic analysis included only 20 genes, of which only two have been reported elsewhere to be related to PSP.  The GP2 study will eventually perform whole-genome sequencing in search of gene variations not previously known to associate with PSP and the other disorders.  To date, the number of DNA samples from under-studied populations remains too small for any results to be reported.
  • The comparison of clinical and autopsy diagnoses shows that while the positive predictive value of a clinical diagnosis of PSP is very good, it could be better.  (The PPV is the percentage of people with the clinical diagnosis who eventually prove to have the disease, in this case by autopsy.) 
  • For most of the Parkinsonian disorders, better biomarkers in living patients are urgently needed.  That, we knew.

One last take-home:  I’d say that the GP2 study shows medical science at its best, combining the latest technology with concern for – and active involvement of – populations and their physicians world-wide.  

Jesse Jackson

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The Rev. Jesse L. Jackson, Sr., the civil rights leader and political activist, has announced that his 2017 diagnosis of Parkinson’s disease has been changed to PSP.

I have no inside information on the details of Rev. Jackson’s condition, but I can tell you that this is a common scenario for people with the second-most-common type of PSP, called PSP-Parkinsonism (PSP-P).  It accounts for about 15% to 35% of all PSP, depending on the source of the data, and starts out looking like Parkinson’s disease (PD), typically with asymmetric stiffness of the limbs and often a tremor, without much cognitive, eye movement or balance difficulty.   The symptoms, like those of PD, usually respond to levodopa, though not quite as well or for as many years. 

PSP-P progresses at a rate typical for PD, not the faster rate for most types of PSP.  The average lifespan of PSP-Richardson syndrome (PSP-RS), which accounts for about 45% to 55% of PSP, is about 6 years, while for PSP-P, it’s 9 years and for PSP overall, 7 years.  (The lifespan of people with PD receiving modern treatment averages about 16 years, but many neurologists today don’t know that before levodopa became available in 1970, it was about 9 years, like PSP-P.)

The typical journey of someone with PSP-P starts with a satisfactory response to levodopa.  But the dosage requirement increases more rapidly and balance problems develop sooner than in PD.  After a few years, the neurologist may suspect one of the “atypical Parkinsonian disorders,” examine the patient more closely than at the previous follow-up visits, find the eye movement problem and frontal cognitive issues of PSP, and change the diagnosis.  Often, this re-evaluation is performed by a second neurologist whose opinion was sought by the patient or family member worried about the atypical symptom course and unsatisfactory levodopa response.

So, if Rev. Jackson does have PSP-P, he would now be at about the average (i.e., the median) survival duration.  Of course, about half of all people with PSP-P survive past the median, some for as long as a total of 20 years or even more.

A scientific comment: Keep in mind that PSP-P wasn’t described in the medical literature until 2005 and formal criteria to distinguish among the various (now 10) different PSP subtypes didn’t appear until 2017.  Before then, most people with PSP-P would not have fulfilled the existing formal criteria for PSP, which were published back in 1996.  Therefore, pre-2017 statistics on the prevalence or lifespan of people with PSP refer mostly to PSP-RS, which is the name given in 2005 to what was defined as “PSP” by the 1996 criteria.

Another scientific comment: PSP-RS, PSP-P and the other 8 subtypes all have the same set of microscopical changes in the brain, featuring neurofibrillary tangles of tau protein and tufted astrocytes.  It’s just the sets of locations around the brain that differ to some extent.  We don’t yet know what causes this “cell-type specificity,” but the best theory is that it’s slight differences in the mis-folding pattern of tau, caused by slightly different locations of abnormal attachment of phosphate groups on the protein.

And finally, an editorial comment: Almost all clinical drug trials in PSP only accept participants with PSP-RS.  There are several good reasons for that, but that policy excludes half of all those with PSP, raising the theoretical possibility that any resulting treatment may work only in that sub-type.  I’ll discuss potential solutions in a future post.

Meanwhile, my deepest gratitude to Rev. Jackson for sacrificing some degree of personal medical privacy in the service of increasing public awareness of PSP and my best wishes to him in the journey forward.

Yes, Congress can accomplish something

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Here’s a great step forward: The Energy and Commerce Committee of the US House of Representatives has just approved the “National Plan to End Parkinson’s Act.”  Thanks in part to advocacy by CurePSP and other organizations devoted to the atypical Parkinsonisms, the bill includes not only PD but also PSP, multiple system atrophy, Lewy body dementia, corticobasal degeneration and Parkinson’s dementia. 

For the remaining required approvals, the bill will now proceed to the full House itself, then the Senate, then the President. (I recited that route for my international readers and for my US readers who doodled through civics class.)  Crucially, the bill was passed with full bipartisan support in the committee, which bodes well for its chances the rest of the way.

Here’s video of the committee’s session.

The bill directs the Department of Health and Human Services to create an advisory commission with representation from all relevant Federal agencies and some advocacy and research organizations as well as patients and caregivers.  Each year, the commission would assess the state of research and clinical care and formulate recommendation on how the various relevant Federal agencies could formulate and coordinate further research plans.  It would also interact with similar organizations internationally. A similar bill for Alzheimer’s disease was enacted in 2011 and has been working successfully by all accounts.

The commission would recommend spending levels for the Federal Government to advance these efforts, but the bill provides no funding for the work of the commission itself.  That would have to be absorbed by the existing budget of the Department of HHS.  (This is standard practice when Congress is interested in a specific medical cause.) 

The bill was first taken up by the committee in March, nine months ago.  One of its major advocates has been Congresswoman Jennifer Wexton of Virginia, who was diagnosed with PSP herself last summer and has been working with CurePSP and others to improve awareness of PSP nationally and to raise funding for research.  Here’s a press release from her office.   The lead sponsor of the bill is Congressman Gus Bilirakis of Florida, who has three close relatives with PD, but 167 other House members signed on as co-sponsors.  The Michael J. Fox Foundation has been working tirelessly for the bill.

I know you’ve been waiting for my editorial commentary.  Here it is:  This is great publicity for PSP, and it sure needs it. 

Congresswoman Wexton is the highest-profile celebrity with PSP since Dudley Moore, the British-American comic actor best known for the movies “10” and “Arthur,” announced his diagnosis of PSP in 1998.  His friends organized a star-studded benefit at Carnegie Hall in New York that raised $50,000 for CurePSP but he declined to become an activist in other ways.  (I was his neurologist, and he told me, “I’ll help out, but don’t want to be the poster child for PSP.”) Linda Ronstadt, the popular singer and Rock and Roll Hall of Fame member, announced in 2019 that her longstanding diagnosis of Parkinson’s had been changed to PSP.  She has not yet supported PSP-related activities of which I’m aware.  A few other less-famous celebrities with PSP have advanced awareness and fundraising, and we’re grateful to them and their families.  But when “progressive supranuclear palsy” is mentioned on the floor of the US House of Representatives and included in press releases, that’s rare and valuable publicity.