Cognitive Symptoms – by Sharon Sha, MD

---

Editor’s Note:  These are brief notes from Elizabeth Wong about what she got out of the presentation and what she learned from the Q&A.

Our brains are incredibly complex, relying on systems and specific proteins to function correctly. One crucial protein is called "tau." Normally, tau helps stabilize the internal structure of our nerve cells. But sometimes, things go wrong. When tau protein folds abnormally and clumps together inside brain cells, it disrupts communication and leads to cell damage and death. This process underlies a group of neurodegenerative disorders known as tauopathies.

Neurologist and memory disorder specialist, Dr. Sharon Sha from Stanford University discusses two specific conditions related to tau build up: Progressive Supranuclear Palsy (PSP) and Corticobasal Syndrome (CBS). 

Here are some key points of what I learned from Dr. Sha’s presentation:

Progressive Supranuclear Palsy (PSP) is often recognized by a distinct set of symptoms. PSP is a sporadic occurrence and onset at age 40 or older with a gradual progression of PSP-related symptoms. Doctors look for core features like:

• Eye Movement Problems: Difficulty moving the eyes, especially up and down.
• Postural Instability: Frequent unexplained falls, often backwards, usually starting early in the disease.
• Akinesia: Slowness of movement initiation.
• Cognitive Dysfunction: Issues with planning, decision-making, and changes in behavior.

Interestingly, the underlying brain changes of PSP don't always lead to just the classic PSP symptoms. Sometimes, individuals with PSP pathology might develop conditions like behavioral variant frontotemporal dementia (bvFTD), characterized by personality changes, or non-fluent variant primary progressive aphasia (nfvPPA), which affects speech production.

Microscopically, PSP involves nerve cell loss, scarring (gliosis), and characteristic tau clumps known as neurofibrillary tangles, neuropil threads, and tufted astrocytes.

Understanding Corticobasal Syndrome (CBS)

Corticobasal Syndrome (CBS) refers to a specific collection of symptoms, often including asymmetric movement problems (affecting one side of the body more), muscle rigidity, difficulty performing familiar skilled movements (apraxia), and sometimes muscle jerks (myoclonus) or the feeling that a limb doesn't belong (alien limb phenomenon).

CBS is a syndrome, meaning it's a pattern of symptoms. It can be caused by several different underlying diseases, not just one. While Corticobasal Degeneration (CBD) – another tauopathy with its own microscopic hallmarks like ballooned neurons and astrocytic plaques – is a common cause, CBS symptoms can also arise from PSP, Alzheimer's Disease, Dementia with Lewy Bodies, and others. This overlap makes diagnosis tricky.

The Challenge of Diagnosis

One of the biggest hurdles with tauopathies like PSP and CBD is diagnosis. Currently, a definitive diagnosis often requires examining brain tissue after death. While researchers are actively developing tools like specialized PET scans to visualize tau in the living brain, and analyzing spinal fluid markers (like MTBR-tau243), these methods are still evolving and have limitations. This lack of specific, reliable biomarkers during life makes differentiating these conditions challenging.

Managing Symptoms and Looking Ahead

While we don't yet have cures for PSP or the underlying causes of CBS, current treatments focus on managing symptoms to improve quality of life. This often involves a team approach:

• Speech Therapy: To help with communication and swallowing difficulties.
• Occupational Therapy: To adapt daily tasks and maintain independence.
• Physical Therapy: To help with balance and mobility.
• Medications: Such as SSRIs, which can sometimes help with mood and behavioral symptoms (though Parkinson's medications are often less effective than in Parkinson's disease itself).

Hope Through Research

The good news is that research is ongoing. Scientists are working hard to understand tau biology better and develop drugs that could potentially target the abnormal tau protein directly – perhaps by preventing it from clumping or helping clear it away. Several clinical trials investigating new tau-targeting therapies are underway. Participation in these trials is vital for advancing our understanding and finding effective treatments.

Understanding PSP, CBS, and other tauopathies is the first step towards better support, improved diagnostics, and ultimately, finding cures. Awareness and continued research efforts offer hope for individuals and families affected by these challenging conditions.

Question and Answer

Question: What difference in treatment would there be if a patient had PSP versus CBD versus other parkinsonism disorders? 

Answer: If it's really for Parkinsonism, if the symptoms that have to do with what we might see in Parkinson's disease like the tremor, stiffness, slowness, there wouldn't be a different treatment essentially. We might offer Sinemet® (carbidopa-levodopa) which tries to enhance dopamine in the brain and body to see if that works. It really doesn't target that tau protein. It's not really what we call disease-modifying therapy. It's really to help the symptoms, and it doesn't always work. There would be no difference in targeting the parkinsonism symptoms. 

Question: Any difference there in terms of treatment for PSP and CBD? 

Answer: No, I think it depends on the syndromes and the symptoms. If someone has more of a swallowing difficulty, which we often see in PSP, we might focus on the speech therapy, evaluating the swallowing, and making sure we're keeping an eye on that. Compared to someone who has CBD who may have more of a cognitive profile. Therefore, it really depends on the symptoms. If the symptoms are very much the same, then I would target the treatments the same way. 

Question: Okay, it sounds like you treat the symptoms, not the disease. 

Answer: Yes. If we are thinking of a clinical trial that's targeting the protein, then maybe we'd have a little difference, but we're not quite there yet. 

Question: Is double vision common in PSP? 

Answer: Not double vision exactly, but difficulty with your vision is common. There can be subtle vertical eye movements, where there's slow velocity of eye movement. So it may be hard to read, and it may not represent exactly as a double vision, but it may be that it's hard to see those letters or combine those letters or it may be hard to move your eyes fast enough. Often people worry about driving or if they're an avid biker, are you able to look and move your eyes fast enough to the side of the road? I often refer to neuro-ophthalmology to really assess where the eyes are moving and whether prism glasses can be helpful and kind of minimizing a double vision or helping you see your full spectrum. 

Question: People want to know what a square wave jerk is and is it specific to CBD or PSP? 

Answer: When a neurologist is examining your eyes to really look for any abnormal eye movements, a subtle form of an eye movement abnormality would be the square wave jerk. If you're just looking and having them stare, the eyes are moving in this sort of square motion. It's really subtle and that doesn't necessarily mean anything, but it can suggest that there may be the beginnings of an eye movement difficulty. Patients may not even describe that they're having difficulty with their eyes at all. It just might be something that kind of fits with PSP or CBD and leads the provider to think that there's a tau protein involved. It's not specific to PSP or CBD, but we've seen it described in literature with PSP because classically there's an eye movement problem with PSP. If I see square wave jerks, I would probably think about an underlying tau protein problem that's not specific to CBD or PSP. 

Question: We are getting a lot of questions about the hummingbird sign on an MRI.

Answer: I didn't talk about MRI pictures because it's so non-specific. But if we were in the clinic and we wanted to help diagnose and we have a picture of the brain, we want to see the shape of the brain. Oftentimes in PSP, the part of the brain that tends to shrink or atrophy is the brainstem and the midbrain. When the midbrain shrinks and we see atrophy, it may be easiest to look at a side view, what we call a sagittal view of the brain, and the brainstem looks a little bit like a hummingbird. Normally the part of the brainstem, the pons, is like the belly of the hummingbird. Therefore when the midbrain kind of shrinks on the side view, the head of the hummingbird looks more prominent and we have the beak. Whereas in someone doesn't who doesn't have midbrain atrophy, you don't see it as prominently. I will say in discussions with so many neurologists, some of us say, "I never see that," and some say, "I always see that," no matter what diagnosis is going on. It's really non-specific, but what it's trying to look for is that there's underlying midbrain atrophy. 

Question: What do you recommend that caregivers can do in the face of their person with PSP or CBD experiencing apathy? 

Answer: Apathy, it's a really, really hard symptom to treat. When I talk to my colleagues in neuro-psychiatry, even the typical antidepressants that we have, like the SSRIs (selective serotonin reuptake inhibitors), they're not often really giving us that sort of pickup the way we want for apathy. But we often try, so that's where I would try first in terms of medications. If there's an executive function problem like the planning, the multitasking, if someone is to say, "Yes, I want a garden," but then you don't see them gardening. Maybe actually walking them out, having all the tools ready, and having all the features required may help minimize that sort of apathetic syndrome in the sense. They may be a little bit apathetic, but there's more beyond that, so helping with planning and all the steps required. It could be like leading the horse to water so to speak, not that I'm calling anybody a horse, but helping plan and providing the steps might help with engaging a bit more too.

Question: What about lifestyle changes, exercise, socialization, creative activities? 

Answer: There is so much research in degenerative disease, the majority of it in Alzheimer's disease because that's just so prevalent, supporting that a healthy lifestyle is so important. What we eat is a fuel for our body, but also our brain. A Mediterranean heart healthy lifestyle has been the most studied to be really good for the brain. It's really a balanced diet. If we had a pill that gave you a balanced nutrition, of course, we would all take it, but you actually have to do the work. Same thing with exercise. Exercise can help stimulate your blood pumping, but actually when you exercise, BDNF, a brain-derived neurotrophic factor, works like fertilizer for the neurons. But it all takes work. We got to do the work to get into that. Exercising, eating healthy, socializing, keeping our brain stimulated, just being here is a big step towards that because you're getting that education, you're seeing people. Sleeping well is important. There are a lot of research studies that show that when we're sleeping, we're helping sort of clear out bad proteins, so not just the REM sleep, but the non-REM sleep. It's all what our parents told us when we're growing up, you have to eat healthy, sleep well, get outside. We are learning in research how important those things are to keep the brain healthy and help slow down progression.