Tag Archives: acetylcholine

Imaging points to problems — and solutions

Posted on by

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.

Rats join the fight

Posted on by

The best animal model we’ve had for PSP over the last 20 years has been a mouse genetically engineered to carry a mutated human tau gene.  The mutation is typically one of two single-nucleotide substitutions, each found in a form of hereditary frontotemporal dementia.  Such a model has been convenient and productive.  But it would be preferable for a PSP model that a) is in a species with a brain whose circuitry is a bit closer our own, and b) to more closely mimic the pathology of human PSP.  A vivid illustration of the inadequacy of the tau mouse has been the recent failure of two anti-tau antibodies to help human PSP after clear success in slowing progression of pathology in the tau mouse.  Dogs, cats or monkeys present practical and ethical difficulties.  Rats have been a candidate but attempts to create a tau rat have failed.  Until now.

A team at the State University of New York at Buffalo led by Dr. Stewart D. Clark has just created a rat with something resembling PSP.  The lead author was Dr. Gabriella King.  The title of the article, in the European Journal of Neuroscience, says it all: Human wildtype tau expression in cholinergic pedunculopontine tegmental neurons is sufficient to produce PSP-like behavioural deficits and neuropathology. 

The researchers took advantage of the fact that PSP involves a complex cluster of cell bodies in the brainstem called the pedunculopontine tegmentum (PPT; often called in the literature the pedunculopontine nucleus, or PPN).  The PPT uses acetylcholine as its neurotransmitter and provides input to many other brain areas involved in PSP.  A loss of acetylcholine-based connections is a major part of the pathology of PSP.  Damage to the PPT alone causes severe gait and balance problems, and loss of its acetylcholine input to other areas causes many other symptoms.  Attempts are ongoing to develop deep-brain stimulation to the PPT as treatment for the balance problems of PSP and Parkinson’s.

The researchers started with rats that were genetically engineered to readily incorporate any introduced gene into neurons that make acetylcholine.  Then, they put the gene for normal human tau into a kind of virus that readily and safely enters brain cells – called an adeno-associated virus.  It’s a commonly-used laboratory tool.  They injected those viruses into five spots in each PPT and three in a part of each thalamus that projects to the PPT, for a total of 16 injections into each rat’s brain.

A month later, the result was gait and balance difficulties and a loss of reactivity to loud noises (which occurs to a degree in human PSP).  Autopsy showed fewer acetylcholine-making neurons in the PPT, fewer dopamine-making neurons in the substantia nigra (presumably because of a loss of input from the PPT), and abnormal aggregates of tau protein in the brainstem resembling neurofibrillary tangles.  None of these abnormalities occurred in control rats receiving injections of adeno-associated virus carrying the gene for a harmless protein into the same 16 spots.

Clearly, this model is not as convenient as the tau mouse, which can be bred in colonies without a need for 16 carefully placed brain injections.  Another problem is that rats are more expensive to purchase and maintain than mice, mostly just because they’re larger.  But for smaller-scale projects, this is a major advance.  Let’s watch for commercialization of the model and for its utilization by other labs.