Basket Trials and Neurodegenerative Disease – Summary of a PSP, CBS, and AD Study

This research summary, written by medical writer Lauren Stroshane, has been posted here with permission from Stanford’s Parkinson’s Community Outreach.  The summary addresses a drug trial by the UCSF Memory and Aging Center that evaluated an experimental drug, TPI-287 in Alzheimer’s Disease (AD), corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP).  While the drug was not effective, scientists still learned useful things from this “basket trial,” which is a research method used in cancer research.

Here’s Lauren’s summary:

parkinsonsblog.stanford.edu/2019/12/research-summary-basket-trials-and-neurodegenerative-disease/

Research Summary:  Basket Trials and Neurodegenerative Disease
December 5, 2019
by Lauren Stroshane with Stanford’s Parkinson’s Community Outreach

A recent drug trial by the UCSF Memory and Aging Center is the first of its kind for neurodegenerative disorders and represents an exciting new method for evaluating the effectiveness of a single drug on participants with the same underlying biology, but different diagnoses. First used in cancer research, basket trials lump together patients by disease pathology, not by diagnosis or symptoms. The UCSF trial evaluated the effectiveness of a drug, TPI-287, in treating toxic buildup of tau protein in the brains of patients with Alzheimer’s disease (AZ), corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP). While the drug ultimately did not show promise, scientists still drew useful takeaways from the study, and future studies of neurodegenerative disease may benefit from utilizing a basket trial design.

What is a basket trial?

A fairly recent innovation in cancer research, basket trials evaluate the effect of a drug on one underlying mutation that can cause a variety of different cancers [1]. For instance, treatment developed for melanoma has also been shown to treat some forms of lung cancer [2]. Basket trials are an offshoot of precision medicine that helps scientists and clinicians identify which patients are likely to be helped by specific treatments. By lumping patients together into the same “basket,” scientists can evaluate a drug’s effects among a broader group to see if benefits are observed. This is distinct from an “umbrella” trial that contains different arms of study, with patients assigned to separate arms depending on their cancer type [1].

An added benefit of the basket study is that it has the potential to open up future treatment eligibility to a larger patient population.

Why is this important for research in neurodegenerative disorders?

Most patients with a neurologic disease have had the frustrating and time-consuming experience of trying multiple medications before (hopefully) finding one that is helpful for their symptoms. Precision medicine aims to eliminate some of that guesswork, by allowing clinicians to more accurately predict which patients will respond to which medications.

In the neurologic world, basket trials could translate to studying the effect of a drug on a specific brain pathology—rather than on a cancer mutation—among patients with a variety of neurologic diagnoses and symptoms, who nonetheless share the same underlying biology.

The UCSF Memory and Aging Center has adapted this approach to look at different types of dementia which share a common pathology. A type of mis-folded protein called tau is known to accumulate in the brains of people with Alzheimer’s disease (AZ), progressive supranuclear palsy (PSP), and frontotemporal dementia (FTD), among other diseases [3]. Although the symptoms of tau pathology may manifest differently among individuals, the underlying toxic action of the tau protein is thought to be the same.

What did the UCSF study find?

In November 2019, UCSF researchers published results of the first-ever basket trial in neurodegenerative disease, which included 95 participants with AZ, PSP, and CBS, and evaluated their response to the drug TPI-287 [3]. This was a safety and feasibility study, to make sure the drug did not harm participants; if well tolerated, it was hoped that TPI-287 would repair some of the damage caused by abnormal tau in the brain.

While results showed that the drug was ultimately not helpful to treat any of these diseases, the researchers did learn some important takeaways [4]:

TPI-287 caused significant allergic reactions in participants with AZ, but not in those with CBS or PSP. This may be due to the difference in risk factors between these diseases: AZ involves the immune system and carries different genetic risk factors than either CBS or PSP.
Some medications that aim to treat tau pathology may not affect all patients with tau disease the same. Further research will help to identify these differences and make such treatments more useful.

What comes next?

The basket approach proved useful in this study, and the UCSF Memory and Aging Center is continuing to deploy it in further research. Another basket trial is currently underway to evaluate the effects of drug BIIB092 (Gosuranemab) on patients with tauopathies including CBS, primary progressive aphasia (nonfluent variant), tau mutation carriers, and chronic traumatic encephalopathy [5].

Researchers are optimistic that continued use of basket trials will help to speed the progress of research into other exciting therapies for neurodegenerative disorders.

 

Reference List:

[1] Clinical trial design and methodology. American Society of Clinical Oncology. https://www.asco.org/research-progress/clinical-trials/clinical-trial-resources/clinical-trial-design-and-methodology Accessed on December 3, 2019.

[2] Weiler N. ‘Basket’ trials for dementia aim to bring precision medicine to neurodegenerative diseases. UCSF press release. https://www.ucsf.edu/news/2019/11/415901/basket-trials-dementia-aim-bring-precision-medicine-neurogenerative-diseases Published on November 11, 2019. Accessed on December 3, 2019.

[3] Medina M. An Overview on the clinical development of tau-based therapeutics. Int J Mol Sci. 2018 Apr; 19(4): 1160. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979300/ Accessed on December 3, 2019.

[4] Tsai RM, Miller Z, Koestler M, et al. Reactions to multiple ascending doses of the microtubule stabilizer TPI-287 in patients with Alzheimer disease, progressive supranuclear palsy, and corticobasal syndrome. JAMA Neurol. 2019 Nov. https://jamanetwork.com/journals/jamaneurology/article-abstract/2753779 Accessed on December 3, 2019.

[5] Boxer A. BIIB092 in primary tauopathies: CBS, nfvPPA, sMAPT, and TES (TauBasket). ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT03658135 Accessed on December 3, 2019.

 

Swallowing, Eating/Chewing, Taste/Smell, etc – Notes from Speech Therapist

Courtney Lewis, a speech pathologist in Australia, spoke recently to the FTD (frontotemporal degeneration) support group in Hawthorn. She addressed swallowing, eating/chewing, oral behaviors (common in the behavioral variant of frontotemporal dementia), taste/smell, and taking medication. Helpful notes from the meeting were taken by Wendy Kelso. I read these notes on the FTD Support Forum, posted by online friend Glen, whose late wife had semantic dementia. Wendy has given permission for these notes to be shared.

Note: I’ve left in all the Australian spellings and terminology (eg, “swallowing tablets” for “swallowing medication”).

Robin

———————————————

Summary of Discussion with Courtney Lewis, Speech Pathologist
FTD Support Group, Dementia Australia Hawthorn
1st November 2019
Minutes: Wendy Kelso

SWALLOWING

– Swallowing is a highly complex activity that requires planning and co-ordination of a number of brain regions
– Controlled by motor cortex – muscles/movement
– Orbitofrontal cortex – behaviour
– Precentral gyrus – voluntary initiation of the swallow reflex
– Brain stem – cranial nerves
– When you swallow, the airways are closed to prevent food going down
the wrong way
– If the windpipe does not properly close off, or if swallowing is not well coordinated, choking can occur
– Aspiration pneumonia can occur if food enters the lungs
– Malnutrition and dehydration may occur as a result of swallowing difficulties

To help the swallowing reflex:

– Verbal instructions usually don’t work – better to use tactile (touch) cues to swallow
– Tap or stroke the persons chin or cheek gently to encourage swallowing
– Take little sips of water when the person has the sensation in their mouth
– Put a cold spoon on their lips to open the mouth to allow them to be fed
– Sometimes people have forgotten what to do next after chewing and need prompting to swallow
– Try and provide food that needs less chewing – steak/tough meat requires too much chewing and is effortful to swallow
– If the mouth is overfull, this affects swallowing
– Try and encourage smaller mouthfuls of food to assist swallowing

EATING/CHEWING

– Brain changes in FTD cause changes in eating, drinking, chewing and swallowing behaviour
– Many people consume food and drink to excess and cannot control their food intake
– They may consume large quantities of sweet foods, sweet drinks and/or alcohol and cigarettes
– They may eat items that are unpleasant or non-food items, such as soap
– Sweets have a high reward centre in the brain – quickly sends pleasure information to the brain
– If the person doesn’t chew their food, it usually reflects frontal/behavioural changes rather than a problem with swallowing

Eating Tips:

– Change the environment – reduce the volume of food/drink and the number of options
– Provide healthy food options in portion controlled sizes
– Never have a buffet meal if the person overeats and cannot monitor their food intake
– Use smaller spoons, plates, cups and wine glasses
– Routine helps – regular meal times in the same place using the same cutlery and crockery. This helps the person recognise it is meal time
– Using hands to eat and finger food is fine – it can assist people to remain independent at feeding for longer
– Changing the temperature and texture can assist the food to go down
– Soup can make the food more moist
– Some people will require 1:1 supervision with meal times to assist the process and ensure safety
– Chewing requires a lot of effort – it is a form of exercise
– Sometimes people become breathless when chewing and this can lead to aspiration
– Fatigue affects chewing and swallowing

ORAL BEHAVIOURS

– Common behaviours include lip smacking, lip chewing and tongue clicking
– Strategies can include sucking or biting items such as a soft piece of fabric or using ‘chewy tubes’
– Chewy tubes are highly tactile and can be in the form of a necklace or bracelet
– If the person licks their lips, try using lip balms or chapsticks
– If the person tongue clicks or thrusts, try and reduce the sound
– If the person is a smoker, this can leave their mouth feeling very dry and they can exhibit a variety of oral behaviours
– Try and encourage sips of water

TASTE AND SMELL

– Changes to taste and smell are caused by changes in the frontal and temporal lobes in the brain
– These changes are very common in bvFTD
– The olfactory bulb (smell) is usually working but the information is not being relayed back to the other areas of the brain that control smell
– Sweet foods are highly desirable as they have a stronger more pleasant taste and have a high reward and value system in the brain
– People with FTD find it difficult to process sour/bitter and disgusting foods
– As an example, broccoli and cauliflower have a ‘negative’ taste, so is less palatable than ice cream to the person with FTD

SWALLOWING TABLETS

– Sometimes swallowing tablets with ice-cream, yoghurt or custard can help
– Many people will find it very hard to swallow tablets with water/liquid
– Swallowing tablets with water is a complex multi-step task and requires more co-ordination

Red flags suggesting atypical parkinsonism, and treatment of DLB, MSA, PSP, and CBD

In a recent issue of the “Handbook of Clinical Neurology,” a chapter is devoted to the four atypical parkinsonism disorders — dementia with Lewy bodies (DLB), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). The authors — both movement disorder specialists at the University of Florida — indicate that “diagnosis is critical as the atypical parkinsonisms herald symptom profiles and prognoses distinct” from Parkinson’s Disease (PD). They also indicate it’s important to identify the suspected underlying pathology — whether it be alpha-synuclein (for DLB and MSA) or tau (for PSP and CBD). Identifying the underlying pathology influences clinical trial enrollment.

Here’s a link to an abstract on PubMed about the chapter:

https://www.ncbi.nlm.nih.gov/pubmed/31753139
Recognizing and treating atypical Parkinson disorders.
Armstrong MJ, McFarland N.
Handb Clin Neurol. 2019;167:301-320.

(There is a $32 fee to download the full article.)

The authors, Drs. Melissa Armstrong and Nikolas McFarland, point out that one reason to know whether you are dealing with an atypical parkinsonism disorder rather than PD is that the survival time is less than 10 years on average and that most die from disease-related issues such as falls, aspiration pneumonia, and failure to thrive.

This statement of concern about caregivers is interesting:

“Given patients’ mounting disability over time and the need for increasing support for both instrumental activities of daily living and basic activities of daily living, caregiver support is critical. In some circumstances, clinicians will need to assist couples in identifying backup caregivers to prepare for the possibility that older caregivers may themselves experience health concerns.”

PHARMACOLOGIC TREATMENT

Pharmacologic treatment is entirely symptomatic, and includes:

MOTOR

* Parkinsonian symptoms: levodopa

* Dystonia: dopaminergic agents; botulinum toxin injections; anticholinergic agents (in younger people with MSA)

* Myoclonus: valproic acid, levetiracetam, clonazepam

The authors note that deep brain stimulation is “rarely helpful” to those with atypical parkinsonism.

NON-MOTOR

* Depression: avoid tricyclic antidepressants in those with orthostatic hypotension

* Depression and Pain: duloxetine

* Depression, Sleep, and Weight Loss: mirtazapine

NONPHARMACOLOGIC TREATMENT

Nonpharmacologic treatment is focused on dysphagia (swallowing problems) and fall prevention. Treatment also includes physical therapy, occupational therapy, and speech-language pathology.

“The role of exercise in the atypical parkinsonisms is not well-researched to date, but increasing evidence of the benefits of exercise in people with PD suggests that there may be an important role for exercise in the atypical parkinsonisms, as well. Safety is a priority and guides selection of appropriate physical interventions.”

The authors encourage neurologists to discuss advance care directives with patients and families early on so that personal preferences are known. These directives should be re-discussed along the way. Palliative care and hospice can be helpful.

The chapter includes a helpful table for physicians on “Red flags suggesting an atypical parkinsonism.” That’s copied below.

Robin

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Recognizing and treating atypical Parkinson disorders.
Armstrong MJ, McFarland N.
Handb Clin Neurol. 2019;167:301-320.

Table 16.1
Red flags suggesting an atypical parkinsonism (a)

Red flag Suggested atypical parkinsonism
Rapid disease progression Any atypical parkinsonism
Lack of a robust levodopa response Any atypical parkinsonism
Bilateral symmetric parkinsonism DLB, PSP
Early gait impairment, falls Any atypical parkinsonism (b)
REM sleep behavior disorder DLB, MSA
Early bulbar dysfunction PSP
Irregular, jerky tremor MSA, CBD
Myoclonus MSA, CBD (less common in DLB, PSP)
Supranuclear gaze palsy PSP, CBD
Dysautonomia DLB, MSA
Cerebellar signs MSA
Laryngeal stridor MSA
Perioral/facial levodopa-induced dyskinesias MSA
Early dementia DLB, PSP, CBD (b)
Apraxia of speech or progressive nonfluent aphasia PSP, CBD
Apraxia CBD, PSP
Alien limb phenomenon CBD
Higher cortical findings (e.g., agraphesthesia) CBD

(a) Most commonly associated diagnoses are listed but this does not exclude the possibility that an unlisted atypical parkinsonism could be associated with the red flag (for example, RBD is described as occurring in people with PSP, but it is more commonly associated with the synucleinopathies).

(b) Specific details of impairments may suggest a specific atypical parkinsonism.

CBD, corticobasal degeneration; DLB, dementia with Lewy bodies; MSA, multiple system atrophy; PSP, progressive supranuclear palsy.

3-step Framework for Diagnosing Dementia (Brad Dickerson, MD)

In this five-minute video, Brad Dickerson, MD, a neurologist at Mass General, describes a 3-step framework for diagnosing dementia:

www.mdmag.com/peer-exchange/early-diagnosis-dementia/recommendations-for-diagnosing-alzheimer-disease

Here are excerpts from the transcript:

Currently, I think we advocate for a 3-step framework that starts by describing the person’s overall cognitive functional status. What we mean by that is, does the person have mild cognitive impairment? Does the person have dementia? … What we really need to do is interview the person and, ideally, an informant, and find out what they are lacking in terms of independent functioning. What have they lost? What do they need help with?

[This] ultimately has major implications for the care plan. Establishing whether the person has mild cognitive impairment or dementia is very important, and I think that threshold varies from person to person and can be quite an arbitrary decision that really takes some clinical experience. Ultimately, what I like to ask people is, if you, as the care partner, can leave the person and go on a trip for a weekend or a week, would they function independently at the things that they need to try to get done to get by in daily life? If the care partner says, “No, I would never do that,” you can pretty comfortably say that the person probably has crossed the threshold into dementia. I think that’s the starting point, No. 1.

No. 2 is, what’s the particular cognitive behavioral syndrome that the person is experiencing? …[Is] the main problem memory loss? Is the main problem executive function? Is the main problem language? Are there multiple problems? A lot of times we see, I think, this common presentation of a person who has memory loss. They’re just not holding on to information, and they also have executive dysfunction. They’re not able to reason. They’re not able to perform tasks to the level that they used to be able to in order to get the job done to reach goals in a valid way.

I think that the syndrome is really meant to capture the major symptoms and signs that the person has of their illness. And that communicates important information to our colleagues and to the patient and family about where their problems are. I think it also allows you to highlight…what their strengths still may be. If this person has a primary memory loss syndrome but their executive function is still good, maybe they can make use of strategies to compensate for some of the problems that they’re having with memory. If they have executive dysfunction, they’re probably not going to be able to do that. Ultimately, that cognitive behavioral syndrome, that second level of specificity in our diagnostic formulation, communicates, in shorthand, to us and to others what the person’s problems are and maybe what they can still do.

And then the third level is, what’s the brain disease that is the cause of the problem? Sometimes it’s multiple diseases. Often, it’s compounded by other medical problems or things like medication effects that affect brain function but are not necessarily a disease in and of itself. The most common, I think, is Alzheimer disease mixed with cerebrovascular pathology in an older adult population—people over the age of 70, 75. In the younger people, I think it can sometimes be a more pure condition, whether it’s Alzheimer disease, or frontotemporal degeneration, or Lewy body disease. Those can often be primary diseases, especially in younger people.

That’s really the 3-step formulation that we advocate that we try to follow. It’s not always possible to be 100% confident in any 1 of those levels, and I think that’s where we have to talk about likely due to Alzheimer disease or likely due to cerebrovascular disease, and rate our level of certainty so we can think about whether we need some additional specialty involvement. If so, what does that involve, and how important is that in thinking about the management? We don’t necessarily have to have the sophisticated biomarkers that we talk a lot about in every individual with dementia likely due to Alzheimer disease. I think there are plenty of people we can all diagnose with fairly straightforward assessments and tests and not do the multimillion-dollar work-up on, that we often end up spending time talking about in the more specialized cases.

 

“FTD talk” fact sheets on PSP and CBD plus BSN’s top resources lists

FTD talk (ftdtalk.org) is a website run by a group of scientists investigating frontotemporal dementia (FTD) at the University College London Institute of Neurology in the UK.  The site’s focus is on the behavioral variant of FTD.

However, they have one-page fact sheets on PSP and CBD:

“What is corticobasal syndrome?”
www.ftdtalk.org/ftd-factsheets/factsheet-9-what-is-corticobasal-syndrome/

“What is progressive supranuclear palsy?”
www.ftdtalk.org/ftd-factsheets/factsheet-10-what-is-progressive-supranuclear-palsy/

These aren’t my favorite resources on PSP and CBD but there may be some value in a one-pager.

The resources we do like are here:

PSP Top Resources
www.brainsupportnetwork.org/education/progressive-supranuclear-palsy/#resources

CBD Top Resources
www.brainsupportnetwork.org/education/corticobasal-degeneration/#resources

Robin