Monthly Archives: October 2023

London calling, again

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Three more encouraging reports from the Neuro 2023 conference jointly sponsored by CurePSP and the PSP Association of the UK, held in London on October 19 and 20.

  • In a series of 48 people with corticobasal syndrome (CBS) during life who had brain autopsies, the underlying pathology was actually corticobasal degeneration (CBD) in 16 (33%), PSP in 14 (29%), Alzheimer’s disease in 6 (13%) and other conditions in the rest.  Similar results have been found many times before, but this study analyzed the neurologists’ office notes and found that actual CBD pathology was most likely in patients with gait freezing as one of the first symptoms.  Among those without early freezing, CBD was most common in those with no early speech problems and onset before age 66.  Those with PSP pathology tended to have had early speech difficulty and onset after age 61.  These observations could be useful to neurologists in separating CBD from PSP during life for purposes of prognostication and treatment trial enrollment. (Ikuko Aiba, et al., Higashinagoya National Hospital, Japan)
  • In 2018, the TRIM11 gene on chromosome 1 was identified as the location of a variant influencing the onset age of PSP, but the precise molecular mechanism underlying that effect remained unknown.  Now, researchers have teased out a single nucleotide variant in an intron (a section of the gene regulating the rate of manufacture of the protein it encodes rather than its amino acid sequence) of TRIM11.  They found that the protein encoded by TRIM11 tags abnormal tau for degradation by the 26S proteasome, which is one of the cell’s garbage disposal systems, and that the variant reduces the production of that protein. This means that somehow stimulating TRIM11’s expression (the rate at which it encodes its protein) could slow the spread of abnormal tau and the progression of PSP. (Sumi Bez et al, University College, London, UK)
  • The drug ezeprogind (previously called AZP2006) has shown favorable results in an early-phase test for safety in people with PSP.  The trial was too brief and small to establish efficacy, but the sponsor, Alzprotect of Loos, France, notes “very promising trends” in slowing progression of the disease.  The orally-administered drug works by reducing inflammation and by improving the action of the lysosomes, one of the cell’s garbage disposal mechanisms.  It will now enter a 120-patient efficacy trial using slowing of progression on the PSP Rating Scale after 12 months as its primary outcome measure.  Half of the 24 trial sites will be in the US and half in Europe.  A start date has not been announced. (Noelle Callizot, et al, Alzprotect, Loos, France)

. . . and the hits keep on coming

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As promised, another installment of new research tidbits from Neuro 2023, held in London from October 19- 23, 2023 and co-sponsored by CurePSP and the PSP Association of the UK:

  • Now that inflammation has come under suspicion as an important part of the pathogenesis of PSP and other tauopathies, researchers have realized that many of the known or suspected risk factors for PSP include an inflammatory component.  These include bacterial infection, repetitive mild head injury, seizures, and autoimmune disease. (Karen Duff, University College London, UK)
  • The PROSPECT-M-UK study of the atypical Parkinsonisms, based in London but involving 29 centers throughout England and Wales, has been funded since 2015. This long-term observational study’s overall goal is to find diagnostic markers.  It has recruited 1,472 patients so far, of whom 661 have PSP.  Participants undergo neuro exams, receive brain imaging, and provide samples of blood, spinal fluid, and DNA.  (Riona Fumi, UCL, UK)
  • A form of tau protein known for 25 years is “high-molecular-weight tau.”  What makes it heavy is the inclusion of a couple of optional stretches of amino acids.  It turns out that this form of tau is more likely than ordinary tau to spread through the brain (called “seeding capacity”), and that the prevalence of HMW tau in various brain regions correlates well with the vulnerability of those regions to PSP. (Ivan Martinez-Valbuena, Rossy Institute, University of Toronto, Canada)
  • Previous comparisons of genetic variants between PSP and controls has revealed five genes that each contribute a bit to PSP risk.  Now, a sixth such gene, called C4A, has been discovered in the largest such study ever, including 2,779 patients with PSP and 5,584 controls.  C4A is involved in an important part of the immune system called the “complement cascade,” and is most active in the oligodendrocytes, one type of the brain’s glial cells. (Kurt Farrell, Mt. Sinai School of Medicine, New York, US)

More progress, more hope

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Sorry for the absence.  I was on vacation in the UK leading up the Neuro 2023 conference in London, co-sponsored by CurePSP and its British counterpart, the PSP Association.  Despite its generic name, the meeting was specifically on PSP and CBD.  But it did cover new developments in everything from DNA to lifestyle.  A few of the more interesting things I heard, and I’ll have another equally pithy batch for you soon:

  • There’s is good evidence that the protein misfolding starts in the intestine and migrates to the brain in Parkinson’s disease, but this seems not to be the case in PSP.  There’s little misfolded tau in the gut in PSP and it’s in a different form than misfolded tau in the brain. (Wendy Noble, University of Exeter, UK)
  • An infrastructure for a “rolling platform” trial is expected to be funded by the NIH as soon as a new federal budget is approved.  That’s where multiple medications are tested in parallel and all use the same placebo group.  This greatly reduces each participant’s chances of receiving a placebo.  It’s “rolling” because as one drug either succeeds or fails, another can replace it without disrupting the overall protocol. (Adam Boxer, UCSF, USA)
  • In PSP, inflammation is found in direct proportion to brain cell damage in the same areas.  This is further evidence that inflammation is an integral part of the pathogenesis of the disease. (Nigel Leigh, Brighton and Sussex Medical School, Brighton, UK)
  • Some drug companies contemplating PSP treatment trials are starting the process by studying the “patient journey” to determine how best to evaluate the effectiveness of their drugs. (Stephanie Oscarson, SJO Research and Consulting, Valley Forge, PA, USA)
  • A new way to measure drug trial outcome is “artificial intelligence-curated music therapy.”  That’s where a trial participant listens to various kinds and volumes of music with EEG electrodes in place on the scalp.  Then an AI algorithm selects the music that optimizes the frequencies and locations of brainwaves known to be associated with a feeling of wellbeing. (Colin Ewen, UCB (Pharma company), Slough, UK
  • Clinical trials expected to start in the next 6-12 months (Günter Höglinger, Ludwig Maximilian University, Munich, Germany)
    • Bepranemab: Anti-tau monoclonal antibody
    • FNP-233 (formerly ASN90): Promotes the attachment of N-acetylglucosamine to tau, reducing its likelihood of misfolding and aggregating.
    • AMX0035 (combination of taurursodiol and sodium phenylbutyrate): stabilizes mitochondrial membranes and improves protein quality-control
    • AZP2006: Improves recycling of progranulin by lysosomes, thereby reducing inflammation
    • GV1001: A fragment of the enzyme telomerase reverse transcriptase, mimicking its anti-inflammatory and other action

Imaging points to problems — and solutions

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Here are two more research presentations from the Movement Disorders Society conference in Copenhagen back in August. These, both pretty technical (sorry!), report on imaging techniques elucidating how the brain is mis-firing in PSP. Both of them offer ideas for new treatment approaches.

Localizing a brain network of progressive supranuclear palsy

E. Ellis, J. Morrison-Ham, E. Younger, J. Joutsa, D. Corp (Melbourne, Australia)

A brain network is a set of areas in the brain that have direct connections with one another and work together to perform a task.  When a neurodegenerative disease like PSP occurs, an important way for the abnormality to spread through the brain is along such networks.  That produces areas of brain cell loss (“atrophy”) in a specific pattern for a specific disease.  These researchers pointed out that in some people with PSP, the “textbook” list of brain areas showing such loss on conventional MRI imaging is not present.  They hypothesize that the usual brain network may nevertheless be abnormal, but without producing enough actual brain cell loss to show up as the full, textbook pattern.  So, they analyzed a database of MRI, PET, and SPECT scans of 363 people with PSP and tabulated the areas of abnormality.  They compared that list to a database of known brain networks that had been compiled using functional MRI in 1,000 healthy people.  (Functional MRI is a standard research technique where a movement or thinking task is performed or a certain sensory input is provided to a person in an MRI machine.  The image is obtained in such a way as to reveal which brain areas’ baseline activity increase or decrease  together in response.)  They found a consistent brain network to be affected in people with PSP, even if conventional imaging fails to show it.  The claustrum, basal ganglia, and midbrain increase their activity, and the cuneus and precuneus reduce theirs.  The authors conclude that their findings “help to reconcile previous heterogeneous neuroimaging findings by demonstrating that they are part of a common brain network.”  

This information could be useful in designing non-invasive, transcranial electrical or magnetic stimulation treatment for PSP.  If the absence (or mildness) of brain cell loss in some patients with PSP means that those cells are still only malfunctioning rather than dying, it could have important implications for development of treatments aimed at rescuing such cells before the damage becomes irreversible.

Topography of cholinergic vulnerability correlates of PIGD motor deficits in DLB and PSP: A [18F]-FEOBV PET study

P. Kanel, T. Brown, S. Roytman, J. Barr, C C. Spears, N. Bohnen (Ann Arbor, USA)

Neurotransmitters are chemicals used by brain and nerve cells to signal to one another across synapses.  Any given brain cell (or related cluster of brain cells, called a “nucleus”) uses a single neurotransmitter type.  One of the more commonly used neurotransmitters in the brain is acetylcholine, and neurons using it are among the most important to become damaged in PSP.  These researchers imaged the brains of patients with PSP using a positron emission tomography (PET) imaging technique that shows acetylcholinergic synaptic activity.  They compared the abnormal areas in each patient to their degree of balance difficulty and gait problems.  They found correlations in basal forebrain, septal nucleus, medial temporal lobe, insula, metathalamus, caudate, cingulum, frontal lobe, cerebellum, and tectum, especially the superior colliculus.  They found that the first areas on this daunting list, the basal forebrain, where the basal nucleus of Meynert is located, is hit hardest and connects to most of the other areas on the list. They conclude that treatment strategies attempting to replace or regenerate damaged neurons for PSP might want to start there.

It’s been known for decades that the basal nucleus of Meynert is heavily involved in PSP and Alzheimer’s disease, but attempts to compensate for the loss of acetylcholine by inhibiting an enzyme that degrades it (using marketed oral medications such as rivastigmine, donepezil, or galantamine) have produced only minimal results.  Perhaps a targeted, surgical approach to regenerating basal nucleus of Meynert neurons using gene therapy could work better.