Tag Archives: positive predictive value

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.  

Good old MRI comes through

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We still don’t have a great diagnostic test for PSP.  The best we can do is about 80%-90% sensitivity, specificity and positive predictive value.  In English:

  • Sensitivity is the fraction of people with PSP who give a positive result on the test.
  • Specificity is the fraction of people without PSP who give a negative result on the test.
  • Positive predictive value is the fraction of people with a positive test who actually have PSP.
  • A single number combining these into something useful in evaluating a single individual — rather than in comparing groups — is the “area under the receiver operating curve” (AUC; see this post for an explanation).  The AUC ranges from 0.50, which is no better than a coin toss, to 1.00, which is perfect accuracy.  An acceptable diagnostic test typically has an AUC of at least 0.85.

Most of the studies of PSP diagnostic markers have important weaknesses such as:

  • The studies frequently set up artificial situations such as distinguishing PSP only from PD or normal aging rather than from the long list of other possibilities that must be considered in the real world.  
  • The patients’ “true diagnoses” are usually defined by history and examination alone rather than by autopsy.
  • The patients included in the study were already known to have PSP by history and exam (or sometimes by autopsy), while the purpose of the marker would be to identify PSP in its much earlier, equivocal stages or in borderline or atypical cases.
  • The patients with PSP in most such studies are only those with PSP-Richardson’s syndrome, who account for only about half of all PSP in the real world.

The best type of marker so far is ordinary MRI.  Recently, a group of neurologists in Athens, Greece led by first author Dr. Vasilios C. Constantinides and senior author Dr. Leonidas Stefanis evaluated the specificity of various MRI-based measurements of brain atrophy.  One strength of their study was that their 441 subjects included people not only with PSP and Parkinson’s disease, but also with a long list of other conditions with which PSP is sometimes confused as well as a group of healthy age-matched controls. 

The single best MRI marker per this study was the area of the midbrain, the fat, V-shaped structure indicated below:

They found that MRI markers provided:

  • High diagnostic value (AUC >0.950 and/or sensitivity and specificity ∼90 %) to distinguish PSP from multiple system atrophy, Parkinson’s disease, and control groups.
  • Intermediate diagnostic value (AUC 0.900 to 0.950 and/or sensitivity and specificity 80 % to 90 %) to distinguish PSP from Alzheimer’s disease, frontotemporal dementia, dementia with Lewy bodies, and mild cognitive impairment (an early stage usually of AD).  
  • Insufficient diagnostic value (AUC < 0.900 or sensitivity/specificity ∼80 %) to distinguish PSP from corticobasal degeneration, normal-pressure hydrocephalus, and primary progressive aphasia (a language abnormality that can be caused by multiple specific diseases).
  • Insufficient value to distinguish the non-Richardson PSP subtypes from corticobasal degeneration and primary progressive aphasia, but good performance in the other comparators.

The researchers also concluded that:

  • One MRI measurement isn’t best for all the possible PSP comparators. 
  • Sometimes a combination of two or three measurements performed better than any single measurement.

One weakness of their method was the use of subjects diagnosed by standard history/exam (i.e., “clinical”) criteria, rather than by autopsy. Another is that their patients with PSP had had symptoms for an average of three years, so these were not subtle or early-stage cases. A letter to the journal’s editor from Dr. Bing Chen of Qingdao City, China further pointed out that the study of Constantinides and colleagues failed to account for the subtle effects of neurological medications on brain atrophy.  As PSP and the comparator disorders may be treated with different sets of drugs, taking this factor into account might enhance or reduce the apparent diagnostic value of MRI atrophy measurements.  

So, bottom line?  Drs. Constantinides and colleagues have given us the first study of MRI markers in PSP to include meaningful numbers of subjects with non-Richardson subtypes.  It’s also one of the few studies of any kind of PSP marker to include comparison of PSP a wide range of diagnostic “competitors” beyond just Parkinson’s and healthy aged persons.  Another plus is that the test, routine MRI, is nearly universally available, relatively inexpensive, and non-invasive.

The hope is that Pharma companies or others with candidate drugs will now have fewer or lower hurdles in the way of initiating clinical trials.