Tag Archives: genetics

The cutting edge (part 1 of 2)

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Here’s the first of two installments summarizing the original, PSP-related research presentations at the annual conference of the International Parkinson and Movement Disorder Society held in early October 2025 in Honolulu. 

The listing is in no particular order and each is followed by my own editorial opinion.  I’ve culled the 29 PSP-related presentations down to the twelve I considered most interesting considering both their scientific importance and their potential interest to this blog’s readers. 

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Clinical Deficits, Quality of Life and Caregiver Burden across PSP Phenotypes

A. Cámara, I. Zaro, C. Painous, Y. Compta (Barcelona, Spain)

Caregiver burden is greater for PSP-Richardson syndrome than for other PSP subtypes, and quality of life showed a statistically non-significant trend for PSP-RS as well.  This information may be useful in counseling patients and caregivers.

LG comment: This result would be expected given the rapid progression of PSP-RS and its high prevalence of falls and dementia relative to most other PSP subtypes.  The study importantly points out that caregiver burden receives too little attention from clinicians, researchers, policy planners and insurors.

Clinical Features Suggestive of Alpha-Synucleinopathy in Progressive Supranuclear Palsy

C. Painous, A. Martínez-Reyes, J. Santamaria, M. Fernández, A. Cámara, Y. Compta (Barcelona, Spain)

Rapid eye movement behavioral disorder and reduced ability to smell are known to be very common in Parkinson’s disease and other alpha-synuclein-aggregating disorders but also occur to some extent in those with PSP.  All of this study’s patients with PD and 10% if those with clinically typical PSP had a positive spinal fluid alpha-synuclein seeding amplification assay (SAA).

LG comment: The new SAA test is not perfectly specific for synucleinopathies and could produce a false positives in people with PSP.  The same is true for RBD and reduced smell sensitivity.

Identification of Genetic Variants in Progressive Supranuclear Palsy in China

Y. Kang, W. Luo (Hangzhou, China)

Pathogenic or likely pathogenic variants consistent with their respective inheritance patterns were detected in 20% (8/40) of patients: three carried PSP-related variants (CCNF, DCTN1, POLG), while five harbored variants in neurodegeneration genes linked to PSP-like phenotypes (AARS1, TDP1, FA2H, TBP, ATXN8).  The controls were only historical controls from the literature.

LG comment: This list of genetic variants, each conferring a very slight increased PSP risk, differs from the lists reported in Western populations, which also have important differences from one another.  The differences could be related to geographically or culturally related environmental contributions (which need different genetic backgrounds to cause damage) or to differences in laboratory methods or choice of non-PSP control populations.

Unraveling the Genetic Architecture of Progressive Supranuclear Palsy in East Asians

P. Chen, R. Lin, N. Lee, J. Hsu, C. Tai, R. Wu, H. Chiang, Y. Wu, C. Lu, H. Chang, T. Lee, Y. Chang, C. Lin (Taipei, Taiwan)

Using a Taiwanese population, this study identified three likely pathogenic variants, in the genes called APP and ABCA7, and the mitochondrial genome.  It also found 39 variants of unknown significance in 37 PSP patients (20.9%), involving  other genes, many of which were already known to confer slight risk for PSP.   

LG comment: The difference in apparent genetic risk factors between Shanghai (previous abstract by Kang et al) and Taiwan underscores the possibility of differences in methodology, although ethnic differences between those two geographical areas could be contributing.  Genetic study of PSP in East Asians could benefit all ethnicities by identifying previously unsuspected cellular pathways involved in the disease.

Multimodal imaging Integrating 18F-APN-1607 and 18F-FP-DTBZ PET in Progressive Supranuclear Palsy

C. Dong, J. Ma, S. Liu (Beijing, China)

Several kinds of positron emission tomography (PET) imaging are being tested for their ability to accurately diagnose PSP.  Two of them were applied concurrently to a group of 20 participants with PSP and a control group.  One, called 18F-APN-1607, shows abnormal accumulation of the tau protein and the other, called 18F-FP-DTBZ, images the neurons that use dopamine.  The result was that 16 of the 20 were correctly identified by the 18F-APN-1607 and three of the other four were identified by the 18F-FP-DTBZ as being probable Parkinson’s disease.  The conclusion is that performing both types of PET could provide more accuracy than the tau PET alone in distinguishing PSP from PD.

LG comment: This result is consistent with the age-old medical principle that there’s no such thing as a perfectly accurate diagnostic test.  Two or more tests measuring different aspects of the same disease can work in a complementary manner to improve diagnostic accuracy.  Fortunately, PET is a nearly harmless, nearly painless test.  Its main drawbacks are time, expense and insufficient availability of many kinds of PET outside of referral centers.

Levodopa response in pathology-confirmed Parkinson’s Disease, Multiple System Atrophy and Progressive Supranuclear Palsy

V. Arca, J. Jurkeviciene, S. Wrigley, P. Cullinane, J. Parmera, Z. Jaunmuktane, T. Warner, E. de Pablo-Fernandez (London, United Kingdom)

About one in three people with PSP experiences some degree of benefit on levodopa, a statistic that prompts most neurologists to give that drug a try.  However, the benefit is often short-lived.  To measure this in a formal way, these researchers reviewed the medical records of autopsy-confirmed patients with PSP, PD or MSA.  Those responding well for over two years were 2% of those with PSP, 86% of those with PD and 8% of those with MSA.

LG comment: The short duration of useful benefit from levodopa in PSP means that each patient enjoying a benefit after the drug initiation should be re-evaluated at each subsequent visit for a continued benefit.  As levodopa can have long-term side effects such as low blood pressure, hallucinations and involuntary movements, a dosage taper carefully monitored by the physician should be considered after the first year or so of treatment.

A dozen at the cutting edge (part 2 of 2)

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Here’s the second of two installments summarizing the original, PSP-related research presentations at the annual conference of the International Parkinson and Movement Disorder Society held in early October 2025 in Honolulu.  I posted the first installment yesterday.

The listing is in no particular order and each entry is followed by my own editorial opinion.  I’ve culled the published 29 PSP-related presentations down to the twelve I considered most interesting considering both their scientific importance and their potential interest to this blog’s readers. 

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Oxidative Stress in Progressive Supranuclear Palsy

P. Alster, D. Otto-ślusarczyk, M. Struga, N. Madetko-Alster (Warsaw, Poland)

The authors measured the concentration of a marker of oxidative stress called “thiobarbituric acid reactive substances” (TBARS) in the blood of 12 people with PSP-Richardson syndrome, 12 with PSP-Parkinson, and 12 healthy controls.  Although oxidative stress is known to be part of the PSP process in the brain, there has been no attempt to compare PSP subtypes in this regard.  The result was that compared to controls,TBARS levels were high in PSP-P but not in PSP-RS.

LG comment: Blood tests for TBARS and perhaps other measures of oxidative stress could become a way to distinguish PSP-P from PSP-RS for purposes of clinical trial enrollment.  If further research supports the finding, potential treatments that reduce oxidative stress would become less attractive for PSP-RS and more attractive for PSP-P.  

Disease Characteristics of the First 100 Participants in the CurePSP Genetics Program Cohort

C. Obasi, V. Zhao, C. Martinez, S. Scholz, H. Morris, N. McFarland, M. Nance, J. Wang, N. Mencacci, B. Cuoto, T. Foroud, J. Verbrugge, A. Miller, L. Heathers, L. Honig, A. Lang, F. Rodriguez-Porcel, P. Moretti, M. Mesaros, J. Brummet, K. Diaz, A. Wills (Boston, USA)

The CurePSP Genetics Program is designed to enroll large numbers of people with PSP, CBS and MSA and to use their DNA samples to find genetic causative factors not discovered by previous, smaller studies.  After the first 10 months, 74 volunteers with PSP have enrolled, 8% percent of whom claim to have a living or deceased relative with PSP. 

LG comment: The authors caution that this project’s stated objective of finding genetic causes of PSP could over-sample people with a positive family history.  On the other hand, some relatives with subtle PSP may have died (without an autopsy) from something else before receiving a correct diagnosis.  So, that 8% could be an under- or an over-estimate.  Enrollment will continue through the end of 2028 and the full genetic analysis should appear in 2029.

Multiscale Entropy: a New Oculomotor Measure of PSP.

C. O’Keeffe, A. Gallagher, J. Inocentes, B. Coe, B. White, D. Brien, D. Munoz, R. Walsh, T. Lynch, C. Fearon (Dublin, Ireland)

The eye movements of PSP are famously reduced in amplitude, but they are also abnormally irregular and complex in a way not evident on a standard neurological examination.  This study used a piece of hardware called “Eyelink 1000+” to measure irregularity (which they call “entropy”) of eye movements during 40 seconds’ viewing of photos of scenery and faces in 24 participants with PSP, 38 with Parkinson’s, and 9 controls. The result was that the irregularity of vertical (up and down) movement in PSP significantly exceeded that in PD and in controls.  Importantly, the degree of eye movement irregularity did not correlate with the overall PSP Rating Scale, suggesting that detectable irregularity could exist even at very low PSPRS scores, at a point in the disease course before a clear diagnosis is possible. The authors suggest that this test could become an inexpensive, non-invasive diagnostic test for PSP valid at even the earliest phase of the illness.

LG comment: Undoubtedly, larger studies will allow calculation of reliable diagnostic statistics such as the “area under the receiver operating characteristic curve” for this test. Equally undoubtedly, the result will be less than perfect. But perhaps this can be combined with other measures of eye movement at the same testing session to provide a combined “PSP eye movement index” with close to 100% sensitivity and specificity.

Spatial Metabolic Covariance Networks in PSP: Implications for Symptomatology and their Neural Basis

B. Wang, W. Luo (Hangzhou, China)

Spatial independent component analysis (ICA) is a statistical technique for finding patterns in images.  This project analyzed FDG PET scans, a map of energy production in the brain, to characterize specific networks of interacting areas that go wrong in PSP. They compared 85 participants with PSP with 70 healthy controls, finding three areas with energy production correlated with aspects of PSP disability. They are a) the dorsomedial thalamus-medial prefrontal cortex (dmT-mPFC) network, causing gait and balance loss; b) the posterior cingulate cortex-lateral prefrontal cortex (PCC-LPFC) network, causing cognitive loss, stiffness and slowness; and c) the putaminal network, causing overall motor control loss.

LG comments: Understanding which sets of brain cells are affected worst in PSP could allow intelligent targeting of future treatment techniques such as deep-brain stimulation and transcranial (i.e., through the intact scalp and skull) magnetic or electrical stimulation.

Validation of the Short Progressive Supranuclear Palsy Quality of Life Scale in PSPNI

Q. Shen, XY. Li, J. Wang, FT. Liu (Shanghai, China)

The PSP Neuroimaging Initiative (PSPNI) is a large, long-term, observational study based in Shanghai, China that investigates far more than just imaging.  Since the 2024 publication by a German group of a short, easy version of the PSP Quality of Life Scale (PSP-ShoQoL), the PSPNI has been investigating its properties.  They now report that the information value of this 12-item scale is similar to that of the original, 46-item version, and its sensitivity to change over a year’s time was good.

LG comment: The FDA has made it clear that a new drug’s ability to improve patients’ quality of life is an important consideration in their approval decisions.  While a more global scale featuring objective neurological findings (such as the PSP Rating Scale or its abridged versions) will continue to serve as the “primary” outcome measure in PSP neuroprotection trials, I expect the new PSP-ShoQoL will soon become first among the “secondary” outcome measures.  (The FDA may base an approval decision on the secondary outcome measures if the result on the primary is good but not dramatic. Similarly, it could approve a drug with multiple favorable secondary measures even if the primary result is borderline.)

Plasma Tau-Species-Containing Neuron-Derived Extracellular Vesicles as Potential Biomarkers for Progressive Supranuclear Palsy

YC. Zheng, HH. Cai, WY. Kou, ZW. Yu, T. Feng (Beijing, China)

Neuron-derived extracellular vesicles (NDEVs) are tiny pieces of brain cells that break away and may enter the spinal fluid or bloodstream.  As tiny, encapsulated “samples” of the parent cell’s contents, NDEVs have been investigated as a sensitive way to measure the molecular contents of those cells.  This project measured concentrations of tau, 4-repeat tau (the kind of tau in the tau tangles of PSP), and tau with an abnormal phosphate at amino acid number 181 (ptau181) in NDEVs in the blood.  The statistical model incorporating these biomarkers yielded an AUC of 95% for distinguishing PSP patients from healthy controls, with a sensitivity of 97% and specificity of 85%, and an AUC of 95% for distinguishing PSP from PD. (The AUC, or area under the receiver operating curve, is a measure of the ability of a single person’s measurement to determine the presence or absence of the corresponding disorder.  An AUC of 100% is perfect, 50% is no better than a coin toss, and over 85% is considered good enough for most purposes.) 

LG comment: These AUCs in the mid-to-high 90s are superb, but so far, assays of NDEVs are technically tricky and not ready for the prime time of regular clinical care.  But I predict that commercial availability will follow soon after other labs confirm this impressive result and extend it to distinguishing PSP not just from PD and controls, but also from CBD, FTD, Alzheimer’s disease and dementia with Lewy bodies.

A dozen at the cutting edge (part 1 of 2)

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Here’s the first of two installments summarizing the original, PSP-related research presentations at the annual conference of the International Parkinson and Movement Disorder Society held in early October 2025 in Honolulu. 

The listing is in no particular order and each is followed by my own editorial opinion.  I’ve culled the 29 PSP-related presentations down to the twelve I considered most interesting considering both their scientific importance and their potential interest to this blog’s readers. 

Clinical Deficits, Quality of Life and Caregiver Burden across PSP Phenotypes

A. Cámara, I. Zaro, C. Painous, Y. Compta (Barcelona, Spain)

Caregiver burden is greater for PSP-Richardson syndrome than for other PSP subtypes, and quality of life showed a statistically non-significant trend for PSP-RS as well.  This information may be useful in counseling patients and caregivers.

LG comment: This result would be expected given the rapid progression of PSP-RS and its high prevalence of falls and dementia relative to most other PSP subtypes.  The study importantly points out that caregiver burden receives too little attention from clinicians, researchers, policy planners and insurors.

Clinical Features Suggestive of Alpha-Synucleinopathy in Progressive Supranuclear Palsy

C. Painous, A. Martínez-Reyes, J. Santamaria, M. Fernández, A. Cámara, Y. Compta (Barcelona, Spain)

Rapid eye movement behavioral disorder and reduced ability to smell are known to be very common in Parkinson’s disease and other alpha-synuclein-aggregating disorders but also occur to some extent in those with PSP.  All of this study’s patients with PD and 10% if those with clinically typical PSP had a positive spinal fluid alpha-synuclein seeding amplification assay (SAA).

LG comment: The new SAA test is not perfectly specific for synucleinopathies and could produce a false positives in people with PSP.  The same is true for RBD and reduced smell sensitivity.

Identification of Genetic Variants in Progressive Supranuclear Palsy in China

Y. Kang, W. Luo (Hangzhou, China)

Pathogenic or likely pathogenic variants consistent with their respective inheritance patterns were detected in 20% (8/40) of patients: three carried PSP-related variants (CCNF, DCTN1, POLG), while five harbored variants in neurodegeneration genes linked to PSP-like phenotypes (AARS1, TDP1, FA2H, TBP, ATXN8).  The controls were only historical controls from the literature.

LG comment: This list of genetic variants, each conferring a very slight increased PSP risk, differs from the lists reported in Western populations, which also have important differences from one another.  The differences could be related to geographically or culturally related environmental contributions (which need different genetic backgrounds to cause damage) or to differences in laboratory methods or choice of non-PSP control populations.

Unraveling the Genetic Architecture of Progressive Supranuclear Palsy in East Asians

P. Chen, R. Lin, N. Lee, J. Hsu, C. Tai, R. Wu, H. Chiang, Y. Wu, C. Lu, H. Chang, T. Lee, Y. Chang, C. Lin (Taipei, Taiwan)

Using a Taiwanese population, this study identified three likely pathogenic variants, in the genes called APP and ABCA7, and the mitochondrial genome.  It also found 39 variants of unknown significance in 37 PSP patients (20.9%), involving  other genes, many of which were already known to confer slight risk for PSP.   

LG comment: The difference in apparent genetic risk factors between Shanghai (previous abstract by Kang et al) and Taiwan underscores the possibility of differences in methodology, although ethnic differences between those two geographical areas could be contributing.  Genetic study of PSP in East Asians could benefit all ethnicities by identifying previously unsuspected cellular pathways involved in the disease.

Multimodal imaging Integrating 18F-APN-1607 and 18F-FP-DTBZ PET in Progressive Supranuclear Palsy

C. Dong, J. Ma, S. Liu (Beijing, China)

Several kinds of positron emission tomography (PET) imaging are being tested for their ability to accurately diagnose PSP.  Two of them were applied concurrently to a group of 20 participants with PSP and a control group.  One, called 18F-APN-1607, shows abnormal accumulation of the tau protein and the other, called 18F-FP-DTBZ, images the neurons that use dopamine.  The result was that 16 of the 20 were correctly identified by the 18F-APN-1607 and three of the other four were identified by the 18F-FP-DTBZ as being probable Parkinson’s disease.  The conclusion is that performing both types of PET could provide more accuracy than the tau PET alone in distinguishing PSP from PD.

LG comment: This result is consistent with the age-old medical principle that there’s no such thing as a perfectly accurate diagnostic test.  Two or more tests measuring different aspects of the same disease can work in a complementary manner to improve diagnostic accuracy.  Fortunately, PET is a nearly harmless, nearly painless test.  Its main drawbacks are time, expense and insufficient availability of many kinds of PET outside of referral centers.

Levodopa response in pathology-confirmed Parkinson’s Disease, Multiple System Atrophy and Progressive Supranuclear Palsy

V. Arca, J. Jurkeviciene, S. Wrigley, P. Cullinane, J. Parmera, Z. Jaunmuktane, T. Warner, E. de Pablo-Fernandez (London, United Kingdom)

About one in three people with PSP experiences some degree of benefit on levodopa, a statistic that prompts most neurologists to give that drug a try.  However, the benefit is often short-lived.  To measure this in a formal way, these researchers reviewed the medical records of autopsy-confirmed patients with PSP, PD or MSA.  Those responding well for over two years were 2% of those with PSP, 86% of those with PD and 8% of those with MSA.

LG comment: The short duration of useful benefit from levodopa in PSP means that each patient enjoying a benefit after the drug initiation should be re-evaluated at each subsequent visit for a continued benefit.  As levodopa can have long-term side effects such as low blood pressure, hallucinations and involuntary movements, a dosage taper carefully monitored by the physician should be considered after the first year or so of treatment.

Testing our metal

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My post from two days ago was about a 2024 paper that had just won an award from the Alzheimer’s Association.  It found and confirmed some subtle genetic risk factors for PSP.  One of them has to do with the part of the immune system called the complement cascade because it complements the role of antibodies. 

The finding on the complement-related gene prompted me to update my theory of the cause and pathogenesis (the subsequent sequence of events in the brain) of PSP.  That includes exposure to metals, at least in some cases. 

In response to that, a commenter asked which specific metals I had in mind. I responded directly in the comments section, but I thought it would make a good post for today:

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We don’t know which specific metals might be involved in the cause of PSP, or how important they would be relative to other causes we don’t yet understand

  • The formal case-control surveys implicating metals asked about metals in general. Besides, that association was weak and lost statistical significance after other exposures were accounted for as confounders.
  • US Army veterans who developed PSP years later were more likely to have frequently fired weapons during their service than other Army veterans without PSP. So that incriminates lead, but gunfire undoubtedly aerosolizes other metals as well. My quick search reveals that gunfire can aerosolize aluminum, antimony, barium, cadmium, chromium, copper, iron, lead, manganese, nickel, tin, tungsten and zinc.
  • The PSP cluster in a couple of adjacent industrial towns in France suggests chromium, but that’s only the most important of the many metals contaminating that environment. Others with circumstantial associations are arsenic, copper and nickel, but others must exist as well.
  • The metals that caused PSP-susceptible cultured neurons to develop tauopathy in a 2020 lab study were chromium and nickel, but other metals weren’t tested because of insufficient lab capability at that time.

So that’s it, and it’s not much. It would be great if the existing genetic risk data could be analyzed for genes involved in metals detoxification. They might have fallen below the threshold of statistical significance for a genome-wide study, but a much more focused gene marker study might be able to show an association with the disease.

It could also be fruitful to analyze available autopsied brain tissue from the French cluster for metals content, comparing it to controls without PSP from the same contaminated area and elsewhere.

Also, let’s not forget that it might take certain combinations of metals, or of metals with other toxins, to increase one’s PSP risk. That could explain why there’s only one known geographical cluster of PSP — that area in France was multiply contaminated.

Thanks for the complement

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The Alzheimer’s Association’s division devoted to frontotemporal dementia and related disorders has just announced its award for best publication of the year for 2004.  It’s entitled, “Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes.” The lead author is Dr. Kurt Farrell of the Icahn School of Medicine at Mt. Sinai in New York, and the senior author is Dr. Adam Naj of the David Geffen School of Medicine at UCLA.  Full disclosure: I played a very minor role in an early phase of the work and am 34th of the 48 co-authors.

The study sought to identify new genes conferring risk for PSP by comparing genetic markers between a group of 2,779 people with PSP (a large majority autopsy-confirmed) and 5,584 people with no neurodegenerative conditions.  This is the largest such study in PSP to date, the first having been published in 2011. The study’s large size gives it greater power to distinguish a genuine PSP-related genetic variant from a statistical fluke. 

This technique can identify not a specific gene, but a small region of a chromosome, typically with 50 to 200 genes.  But the researchers then nominated a couple of the most likely genes in that region and tested brain tissue for excessive amounts or abnormal forms of the protein encoded by the candidate genes.

Besides confirming PSP’s previously-identified genetic risk factors, Farrell and colleagues identified a new risk gene called C4A, located on chromosome 6. The protein it encodes is part of the cell’s “innate immune system.” The C stands for “complement,” a complicated group of proteins that assist the antibodies.  Once an antibody latches onto an unwanted invader like a bacterium or virus, proteins from the complement system attach to the other end of the antibody, initiating a series of interactions that eventually produces an “attack complex” that pokes a major hole in the invader.

The other important finding from the same study was a strong tendency for all the genes known to increase PSP risk to affect the oligodendrocytes.  Those are the brain cells that form the myelin sheath insulating the axons of most of the brain’s neurons, greatly facilitating electrical conduction.  We’ve known for decades that loss of myelin is an early feature in PSP, and that some PSP risk genes encode proteins related to oligodendrocytes.  But the new paper provides important confirmation in a larger patient group, using techniques not previously available.

So, bottom line: Although the genetic basis of PSP is not usually enough to make the disease occur in more than one member of a family, it could still be one important factor, along with things like a poorly-understood toxin exposure.  Furthermore, the new evidence that the oligodendrocytes might be the first cells to get sick in PSP points researchers in that direction in their search for new, easily addressable drug targets.  Plus, the discovery that an important part of the immune system could be what’s ailing the oligodendrocytes means that the array of potential drug targets is now much better focused. Shotgun approaches to taming components of the complement system have been under way for about a decade now, and the new finding of Farrell et al could focus those efforts nicely.

It slices! It dices!

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Yesterday’s post was about the clinical heterogeneity of PSP and how it prompts a theory about the cause(s) of the disease. A couple of hours after I hit “send” I saw a new paper that indirectly supports my idea.

As you probably know, PSP comes in ten known subtypes. The original type, first described in detail in 1963, is called PSP-Richardson syndrome and accounts for about half of all PSP. The other nine have been described since 2005. The new paper reports five subtypes among PSP-Richardson syndrome itself.


The study is from Dr. Mahesh Kumar, a post-doc at the Mayo Clinic, with Dr. Keith Josephs as senior author. They performed statistical tests called “network analysis” and “cluster analysis” on their 118 patients with PSP-Richardson. The five PSP-Richardson “sub-sub-types” emphasize, respectively, tremor; light sensitivity; reduced eye movement (i.e., supranuclear gaze palsy); cognitive loss and slowness/stiffness.


These are not just points on a continuous spectrum. Rather, in each of the five PSP-Richardson sub-sub-types, a group of features and their severities occurs together in individuals in a combination that would not be expected by random combination based their respective frequencies in the total PSP-RS population. For example, people with worse slowness/stiffness tended to have milder eye movement problems and worse cognition than chance would dictate.


Here’s a graphical representation of the results. The features represented by the circles in each group interact with one another in a mutually reinforcing (the black bars) or interfering (the red bars) way. The thickness of the bars represents the strength of the interaction. An explanation in the researchers’ own words follows:

From Kumar et al. Mov Dis Clin Prac 2025
Network Analysis showing 16 signs/symptoms and their associations. Each node in figure represents symptom/sign, Black edges represent positive connection, and red edges represent negative connection; thicker edges represent stronger association.
V1, Sensitivity to bright light; V2, MoCA (Cognition Score); V3, Neck Rigidity; V4, Urinary Incontinence; V5, Emotional Incontinence; V6, Upward ocular movement dysfunction; V7, Downward ocular movement dysfunction; V8, Horizontal ocular movement dysfunction; V9, Eye lid dysfunction; V10, Limb apraxia; V11, FAB (Executive Score); V12, Gait dysfunction; V13, Bradykinesia; V14, Postural tremor; V15, Kinetic tremor; V16, Rest tremor.

All this begs the question as to the basis of the specific groups of signs and symptoms. The answer will probably apply as well to the ten PSP subtypes as to the five PSP-Richardson sub-sub-types. It probably has to do with the specific combination of PSP’s menu of causative factors at work in the individual. As I pointed out in my last post, there are 14 known gene variants contributing to PSP risk and that number is growing. Exposure to toxic metals may also be a factor and those exposures could come at different times of life and in various durations, intensities and combinations. The number of genetic/toxic combinations of these factors sufficient to cause PSP would be astronomical, and the likeliest combinations might account for the likeliest PSP subtypes and sub-sub-types.


Then throw in the stochastic factors, meaning random throws of the dice. I’ll get to that in a future post.

More than the sum of its parts

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The first PSP whole-genome analysis (or WGA) was published in 2011. It found that “markers” associated with each of four genes were more common among people with PSP than among controls without PSP. Those markers were themselves genes of precisely known location on their chromosome but with unknown or irrelevant function. Such a gene is useful as a marker if one specific nucleotide (the A’s, T’s, G’s and C’s of the genetic code) varies among healthy individuals. Such a phenomenon is called a “single nucleotide polymorphism” or SNP, pronounced “snip.”)

So, for example, at a certain location on, say, chromosome 1, the general population might have an A in 70% of people, a T in 20%, a G in 8% and a C in 2%. If that array of frequencies is different (to a statistically significant degree) in the population with a certain disease, it means that the marker gene is located very close to (or sometimes even within) a gene that’s actually contributing to the cause of the disease.

Since then, it has become possible to easily work out the sequence of nucleotides in every gene, which, as you’d imagine, can make it a lot easier to find genetic causes of diseases. But it’s not as easy as it sounds because it’s hard to distinguish a harmless copying error from a disease-causing error. Besides, the statistics required for sequencing studies have not yet been fully invented. So, good old marker analysis is still very important and useful.


Now let’s talk about the cause of PSP. There seems to be some sort of genetic predisposition that increases the risk but is probably not enough to actually cause the disease within a usual human lifespan. So, something else, presumably an environmental exposure, is probably needed. The only such candidate toxins discovered to date for PSP have been metals, though specific metals have not been clearly identified. (There’s also unconfirmed PSP risk for consumption of paw-paw, a fruit harboring a mitochondrial toxin; and well-confirmed incrimination of lesser educational attainment, though how that relates to environmental toxins or to PSP is unknown.)
Each of those four genes identified in 2011 and about 14 others discovered since raises the risk of PSP by only a tiny amount – in the neighborhood of 1-2%. But that figure was calculated separately for each gene. There has been no attempt to work out how the risk genes might interact to raise the PSP risk enough to allow the disease process to get started, with or without an extra boost from some mysterious environmental exposure.


Still with me? I hope so, because I’ve finally gotten to my point.

The current issue of Journal of Neurogenetics includes a paper from a research group in Bangalore, India headed by Dr. Saikat Dey of the National Institute of Mental Health and Neurosciences, with senior author Dr. Ravi Yadav. They looked only at those original four genes identified in the 2011 whole-genome marker analysis, called MAPT (encoding the tau protein), STX6 (encoding for syntaxin, which directs the movement of tiny chemical-filled balloons called vesicles in brain cells), MOPB (encoding myelin basic protein, a component of the layer of insulation around axons in the brain), and EIF2AK3 (encoding PERK, a protein that helps regulate the stress response in brain cells).


Dey et al looked for combinations of these genes’ markers occurring at a greater frequency in PSP than expected by chance given their individual frequencies. (This is called “epistatic” gene interaction.) The strongest result was between MAPT, STX6 and MOBP. The interaction between MAPT and MOBP was almost as strong, and slightly weaker interactions occurred between MOBP and STX6 and between MOBP and MAPT.


So what, you say? This is important because it can explain how gene variants, each of which raises the likelihood of developing PSP only very slightly, can nevertheless cause the disease if they occur together, perhaps even without any ancillary environmental toxin.


This can explain why PSP and other neurodegenerative diseases generally run only weakly in families: It’s unlikely that any two close relatives will share the same combination of gene variants that raise PSP risk.


Here’s a general illustration of what I’m talking about: Suppose a disease occurs with 100% likelihood in anyone with a risk mutation in each of three specific genes and that each mutation by itself has a frequency of only 1% in the population. That means that for someone to develop the disease, they’d need the unlucky combination of three 1% events. That likelihood is 1% to the third power, or 1 in a million. Now, that person’s sibling would have only a 50% chance of sharing the same form of each gene (called an “allele”). So, for each sibling of the person with the disease, the chance of sharing all three disease-causing alleles would be 0.5% to the third power, or 1¼ in 100 million.


Such gene interactions explain how a purely genetic disease could so rarely occur twice in the same family.


I’ve simplified the analysis of Dr. Dey and colleagues, and more important, there are at least another 10 PSP risk genes that their analysis didn’t consider. So, I hope they or someone else gets around to that very soon. Maybe they will find that the cause of PSP can be entirely explained by unusual combinations of mildly risk-conferring genes that can be tested for in a drop of saliva. That has some important ethical implications, but it could permit genetic counseling and could make it much easier to find volunteers with “pre-PSP” on whom to test drugs to slow or halt the disease’s progression. Furthermore, identifying a combination of protein actions that, when deficient, causes PSP could permit targeted design of new drugs.

So, why zebrafish?

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In response to a commenter’s question on how zebrafish became an experimental model: Zebrafish have been systematically used in research since the 1950s, starting with studies of the causes of birth defects. The original reasons for choosing that species were that it takes only four days from fertilization to hatching and that the eggs develop outside the mother’s body. The latter makes it easy to expose the developing embryos to experimental toxins by simply adding them to the water. Even after only a week post-hatching, young zebrafish half a centimeter long display most of the physiological and behavioral features of adults 6-8 times that size. Juvenile zebrafish are transparent, allowing many experimental outcomes to be easily observed without harming the animal or further interfering in its function. Besides, they’re easy to clone as a genetically uniform colony and react to toxins in ways very similar to mammals. Much of the earliest research in developing zebrafish as a genetic model was performed in the 1960s to 80s by George Streisinger, a Holocaust survivor working at the University of Oregon. Here’s a great biosketch.

Vindaloo + hockey = PSP?

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Did you know that Toronto is the most ethnically diverse city in the world?  Besides, it’s a pretty big place, with about 6 million people in its metropolitan area.  Besides that, Toronto is home to one of the top PSP research institutions in the world, the Rossy Centre at the University of Toronto, and Canada has universal, free medical insurance, which removes financial impediments to diagnosis and treatment.  That’s why Toronto is a great place to answer the question as to whether the prevalence of PSP is uniform across groups of different ethnic backgrounds.

Dr. Blas Couto and colleagues have done just that, reporting their results in the current issue of Parkinsonism and Related Disorders.  They tabulated ethnicity for 135 patients with PSP living in the officially designated Toronto area and seen at their center as patients from 2019 to 2023.  The group proved unusual in that only 4.4% had the PSP-Parkinsonism variant, compared with figures elsewhere of around 25% to 40%.  The group with PSP-Richardson syndrome comprised 68% rather than the usual 45% to 55% and the other variants gave the expected percentages.

The ethnicities they considered were actually geographical areas, not exactly race, whatever that is. (“Race” has no scientific definition, anyway.)  The categories were — and this is directly copied/pasted from the paper:

  • East and southeast Asia, including China and Pacific Islands such as Philippines
  • Southern Asia, including India, Pakistan and middle east countries
  • Africa
  • South America, Central America and Mexico
  • West Indies, including Guyana, Haiti, Bahamas, Lesser Antilles such as Barbados, Trinidad and Tobago, Dominica, Grenada, Saint Kitts, Antigua and Barbuda, Santa Lucia
  • Europe, Australia and North America, excluding Mexico.

The analysis compared the frequencies of these demographics to those from the census for people aged 65 and older living in the Toronto metro area. 

The result was that the southern Asia group was moderately over-represented among the patients with PSP.  That group accounted for 11.5% of the general population but 25.2% of the PSP population at the researchers’ center.  That was statistically significant at the <.001 level, meaning that the chance of its being a false-positive fluke are less than 1 in 1,000.

They also compared the six groups to one another with regard to the PSP subtypes, finding the same southern Asia group to include more PSP-progressive gait freezing (17.7%) and PSP-corticobasal syndrome (14.7%) than the European-derived patients (6.4% and 9.5%, respectively). 

Couto et al mention the possibility of some sort of genetic effect, but the literature offers no clues as to what that might be, and they cite three previous papers from the UK showing no difference in PSP prevalence between whites and southern Indians there.  Could something in the food or water in Toronto affect Asians disportionately?  The title of this post offers an unserious possibility, but you get the idea.

Chin-stroking on that aside, now is when the rest of us try to poke holes in the findings.  Here are my efforts:

  • Do the ethnic percentages in their PSP practice or in medical institution as a whole accurately reflect those of the Toronto area?  That would be easy to measure.  I ask because in the US in recent years, the medical profession has acquired a disproportionate representation of people of southern Asian background.  Could that group therefore trust academic physicians more and seek their care more readily than do other ethnic groups? 
  • The patient mix of a highly specialized practice like that at the Rossy PSP Centre is subject to the referral habits of outside neurologists.  Neurologists who feel less comfortable with the atypical Parkinsonisms may be more likely to refer patients.  Perhaps that applies to a few neurologists practicing in heavily southern Asian neighborhoods in the Toronto area.
  • Despite the universal availability of free medical care in Canada, racially-based disparities in health and care access do exist there.  Couto et all cite this article. 
  • This is a univariate comparison, meaning that it didn’t correct for a hypothetical effect of other health issues that might be more common in the southern Asian population.  Not that I know what those might be.
  • Although the analysis age-matched the PSP group with the general population by confining itself to the over-65 group, that may not have been enough. Perhaps working-age people immigrating from southern Asia brought elderly parents with them more often than did those immigrating from elsewhere, thereby skewing the over-65 group towards the 80s and 90s and increasing the measured prevalence of an age-related disease like PSP.

An intriguing finding.  Hopefully this paper will stimulate others to dig deeper. That would be a victory for any scientific paper.

Seek and ye shall find

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This week, our knowledge of the genetics of PSP has more than doubled.  First, as usual, some background:

Like many other complex conditions like atherosclerosis, schizophrenia and most cancers, PSP does run in families a bit more often than expected by chance.  But as in those diseases, the familial tendency is too weak to produce the classic dominant or recessive pattern associated with a single, strongly-acting gene variant as in Huntington’s, Tay-Sachs or sickle cell anemia. Besides, adding up the risks from the known PSP-related genes wouldn’t explain the incidence of the disease in the population, rare though it is.  That has prompted the theory that some unidentified external exposure or experience also has to play a role. 

Over the past 25 years or so, a number of gene variants have been found to confer slight risks for developing PSP.  The first-discovered and still the most important, called the “H1 haplotype,” is a complex set of variants in region of chromosome 17 that includes MAPT, the gene encoding the tau protein. Another four variants on other chromosomes were published in 2011 by CurePSP’s PSP Genetics Consortium. 

In the years since, nine other variants were added piecemeal by other researchers. Those first 14 were all discovered using a technique called “marker association,” which only identifies a region of about 100 genes where the culprit gene would be located.  The gene from those 100 that’s reported as a “hit” is generally the one with the best statistical association with the marker along with a scientifically rational reason to be associated with the disease under study.  A more finely-grained search would actually work out the sequence of the genetic code, comparing people with PSP to those without PSP.  That wasn’t practical back in 2011, but now it is.  It’s called “whole-genome sequencing” or WGS.

The new list of gene variants has been found by an international WGS collaboration that grew out of the original CurePSP-supported team.  They used DNA samples from 1,718 people with PSP, of whom 1,441 were autopsy-confirmed, and 2,944 samples from people without PSP as controls.  The leaders are at the University of Pennsylvania and UCLA, but 26 other research institutions in nine countries contributed.

They confirmed five of the six previously-identified variants (the sixth came very close) and added seven new ones. They also elucidated new details of the cluster of variants in the H1 region.  Most remarkably, they confirmed a previous, smaller study showing that PSP reverses the relationship of Alzheimer’s disease with the ApoE gene on chromosome 19.  In AD, the epsilon 4 variant of ApoE is over-represented relative to controls and the epsilon-2 variant is under-represented, while in PSP, it turns out that those proportions are reversed despite the fact that both AD and PSP are tauopathies.

So far, the research article is only posted on medRxiv (“med archive”), a website for manuscripts not yet through the peer review process at a journal.  (But my brain’s blogging center couldn’t restrain itself.)  The next steps for the authorship team are to gather online comments on the manuscript from other scientists and to submit the resulting revision to a regular journal.  There, the peer review may dictate other changes.  The next scientific step will be to figure out what the mutations are doing wrong, determine to what extent the variants increase or decrease the amount of the protein they encode (called “expression studies”), and look for proteins encoded by those genes (or for proteins they interact with) that might be modulated by drugs.

As far as I can tell, even the newly expanded list of risk variants doesn’t explain enough of the overall cause of PSP to be used as a diagnostic panel.  But it’s a start in that direction.

My canned lecture on PSP includes a slide on the two dozen or so most important scientific milestones in PSP research since the disease was first described in 1963.  This paper is going there.  As I learn more about the publication progress and clinical implications of this work, I’ll keep you all apprised.