Join and learn from others who understand the FTD journey at this virtual AFTD Meet & Greet event for people in Seattle, Wash., and its surrounding communities on Sunday, February 9, starting at 2:00 p.m. PT.
Email event host Pooja Thorali at [email protected] to RSVP and receive the Zoom link. You can also download this flyer to learn more.
AFTD Ambassador Scott Oxarart invites anyone impacted by FTD to join others on the FTD journey for a two-mile walk beginning at Nevada Veterans Memorial Plaza in Sparks (300 Howard Drive), starting at 10:00 a.m.
If you are unable to walk, reach out to Scott at [email protected] to find a better way to connect.
Download this flyer to learn more.
Denali Therapeutics and Takeda Pharmaceutical Company’s phase 1/2 clinical trial for FTD caused by GRN mutations is opening its first U.S.-based trial site at the University of Pennsylvania (UPenn). The multicenter study is evaluating the safety and tolerability of the drug DNL593 in people with and without FTD.
In FTD-GRN, mutations of the GRN gene cause an impairment of the protein progranulin, which protects neurons in the brain. DNL593 was designed to address progranulin deficits by reintroducing it through an intravenous drip. The experimental drug uses a “protein transport vehicle,” a form of protein that moves others around, to help progranulin safely pass through the protective blood-brain barrier.
Data from preclinical studies of DNL593 showed that it improved progranulin uptake, the process by which cells absorb it from their surroundings. In mouse models, the drug prevented neurodegeneration and dysfunction of glial cells, which serve as the primary immune defense of the central nervous system.
Denali and Takeda began the phase 1/2 study in 2022 with the goal of enrolling 106 participants across the two halves of the study; before coming to the U.S., the trial operated in Europe, Brazil, and Turkey. The first study phase will evaluate single doses of DNL593 in adults without FTD; in the second phase people with FTD will receive multiple, increasingly larger doses (known as a “multiple ascending dose” phase).
The U.S trial site is at the Hospital of UPenn in Philadelphia and is currently recruiting participants who are diagnosed with FTD-GRN for the second phase of the trial.
The second phase is a “double-blind” study, where half of the participants receive a placebo, and the rest the experimental drug. After this phase is completed, Denali and Takeda will proceed with an 18-month “open-label extension,” where all participants will have the option to take the drug. The companies expect to conclude dosing and data collection by November 2025.
For more information on the study, visit the ClinicalTrials.gov page for the trial, or the trial’s Penn Medicine page.
Are you interested in participating in more studies like this? Visit AFTD’s Studies Seeking Participants page to find more actively recruiting trials. And signing up with the FTD Disorders Registry can keep up to date on recruiting studies and let you share your experiences with researchers.
A study published in Nature Medicine finds that a type of particle associated with specific cell subtypes could potentially be utilized as a biomarker for FTD and ALS disorders. The particle, known as an “extracellular vesicle,” contains tau and TDP-43 proteins, which are both altered with FTD-ALS.
Extracellular vesicles (EVs) are naturally released from most types of cells and play a key role in cell-to-cell communication by transporting proteins, lipids, and RNA between cells.
FTD and ALS are proteinopathies, a condition or disease caused by the dysfunction of proteins like tau and TDP-43. While tau levels in the bloodstream can identify people with Alzheimer’s disease early in progression, its use as a biomarker in other tauopathies is hampered by tau fragmentation in fluids outside of cells. Researchers have looked at levels of other pathological forms of tau and TDP-43 in plasma and cerebrospinal fluid (CSF) as biomarkers, with studies underway to make improved assays better capable of detecting the protein in blood and CSF.
However, EVs are known to transport healthy proteins and pathological forms of tau and TDP-43 between cells, protecting them and facilitating the formation of protein clumps that play a crucial role in FTD and ALS. Anja Schneider, MD, and researchers at the German Center for Neurodegenerative Diseases (DZNE) launched a pilot study to evaluate whether tau and TDP-43 levels in EVs could be biomarkers for FTD and ALS disorders.
The pilot study included 704 participants from the DZNE Clinical Register Study of Neurodegenerative Diseases (also known as “DESCRIBE”), including 37 people with genetically confirmed cases. Participants had a diagnosis of either behavioral variant FTD (bvFTD), progressive supranuclear palsy (PSP), Alzheimer’s disease, semantic variant primary progressive aphasia (svPPA), or ALS.
A main area of focus for the study was the proportion of two different forms of tau to one another, known as “three repeat” and “four repeat” tau (3R and 4R) subtypes or isoforms. While 3R and 4R tau levels are typically balanced in healthy individuals, diseases like FTD and ALS can disrupt this and cause one form to become more prominent. Researchers found that the ratio of 3R to 4R tau in bvFTD, svPPA, and Alzheimer’s disease was skewed towards 3R. In PSP, which is associated with 4R tau, the skewed ratio was reversed.
The researchers noted that the ratio reflected disease severity but differed by disorder. For bvFTD, for example, a higher ratio of 3R/4R tau indicated that people experienced more severe symptoms, while a lower 3R/4R ratio was observed in people with PSP.
While there was no secondary protein against which to compare TDP-43, researchers noted that higher levels of pathological TDP-43 in EVs correlated with increased disease severity. TDP-43 levels could also be used to discriminate between disorders similarly to tau; EVs in people with ALS had 45 picograms per milliliter (pg/ml) of TDP-43, while people with PSP and control participants without FTD had approximately 9 pg/ml of TDP-43 on average.
Together, the biomarkers could be used to diagnose bvFTD, which is notoriously difficult to diagnose clinically due to its symptomology, which overlaps with other neurodegenerative diseases and psychiatric disorders. The study authors found that in people with FTD-causing genetic mutations, EVs reflected the proteinopathy associated with the mutation. In people with a C9orf72 mutation, which is associated with TDP-43, the 3R/4R tau ratio was 1.0, while TDP-43 levels were heightened – the opposite was true for people with a tau-associated MAPT mutation, with the tau ratio three to four times higher and TDP-43 reduced.
To validate their findings, the authors turned to a second cohort of participants outside of DESCRIBE, obtaining data from a group of people with FTD who participated in research at the Hospital de la Santa Creu i Sant Pau in Spain. The group included 65 people with ALS, 58 with ALS-FTD, 50 with bvFTD, 41 with PSP, and 23 with an FTD risk gene, as well as 50 without FTD to serve as controls. The researchers discovered that the data from the Spanish cohort, by and large, matched the data from the initial cohort.
While some researchers believe that the tested EVs originate in the brain, there is ongoing discussion about the possibility that they did not. While the origin of the EVs does not matter much for clinical testing, Dr. Schneider noted that finding the origin may be necessary for clinical trials.
“If you want to measure target engagement, then it would be nice to Dr. Schneider told Alzforum. “We need better ways to detect brain-derived extracellular vesicles.”
Are you interested in learning more about the search for FTD biomarkers? In May, the Foundation for the National Institutes of Health Biomarkers Consortium announced that the US FDA accepted its letter of intent to qualify a protein as a biomarker for the onset of genetic FTD symptoms.
Stay updated on opportunities to participate in research by joining the FTD Disorders Registry. The Registry is a powerful tool that connects people with lived experience to studies and allows them to share their insights with researchers, in order to drive FTD research forward.
Incontinence is a common symptom of FTD and other dementias. But for both care partners and persons diagnosed, incontinence can be one of the more difficult symptoms to manage or even talk about, given its associations with private bodily functions and a perceived loss of dignity and independence. As FTD progresses, some persons diagnosed become unable to recognize their illness and may refuse or resist incontinence care or give off the “impression” they don’t care they are having accidents, further complicating matters.
FTD’s behavioral symptoms can contribute significantly to episodes of incontinence. Such symptoms include apathy, disinhibition, compulsive behavior, distractibility, and a lack of awareness about one’s condition (a symptom known as anosognosia) and movement changes. As the disease progresses, a person diagnosed with FTD may lose their ability to respond to the urge to use the bathroom; they may so do in a socially inappropriate location and may try to dispose of it in an unsanitary manner. Care partners should remember that such behavior is a result of FTD and is not done willfully by the person diagnosed.
While managing incontinence in FTD can be challenging for the person diagnosed and their care partner, the following guidelines can offer help:
While the above strategies can help to reduce the frequency of accidents, they may still happen. Accidents are not merely messy – they can, potentially leading to infections. Consider use of incontinent products such as Depends or sanitary pads. Keep on hand nitrile gloves, towels (paper or cloth), wet wipes, soap (hand sanitizer will work in a pinch), and disinfecting spray or wipes. Finally, when out of the house, toilet before leaving and bring a second set of clothing and extra supplies in a plastic bag; you can use the empty bag to store any soiled clothes.
People living with an FTD diagnosis may exhibit an involuntary grasp reflex, making clean-up difficult. Care partners can hand a rolled towel or other small object to the person diagnosed so they have something to grab besides their care partner.
Whether they occur in the home or in public, episodes of incontinence can be embarrassing for the person diagnosed, contributing to depression and feelings of social isolation, both of which are already common in FTD. Care partners therefore should try to remain calm and empathic. But accidents are inevitable. Give yourself grace if you become frustrated. And be sure to reach out to an AFTD support group or the AFTD HelpLine for additional advice, information, or words of encouragement.
To learn more about incontinence management, read Issue #10 of AFTD’s “Partners in FTD Care“. You can also receive additional guidance from the books “The 36-Hour Day,” by Nancy L. Mace, MA, and Peter V. Rabins. MD, MPH, and “What If It’s Not Alzheimer’s?,” edited by Gary Radin and Lisa Radin.
A study published in Science Translational Medicine explores how well the brain imaging tau PET tracer F-MK-6240 (flortaucipir) captures the presence of underlying protein clumps seen in post-mortem Alzheimer’s tissue. It explores how effectively the tracer could be used to recognize early stages of Alzheimer’s disease and detect a similar but separate disorder called primary age-related tauopathy (PART). The study results provide new insights into the tracer’s sensitivity and specificity for tau. These findings can indicate whether a tracer can be used as a “biomarker”, a readout to detect the presence or severity of a specific disease. Biomarkers are critical for accurate and early diagnosis, as well as tracking disease progression and measuring if potential treatments are working in clinical trials.
Like Alzheimer’s disease, corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), both forms of FTD, are associated with the tau protein. They are characterized by the protein’s structure being altered through the process of phosphorylation, which causes abnormal accumulations of the tau known as neurofibrillary tangles. Primary age-related tauopathy (PART) is yet another disorder which also has tau clumps but is not FTD or Alzheimer’s. Collectively, these disorders are known as “tauopathies”, but may differ between the type of tau, the amount, the location, and the types of other disrupted proteins. Thus, imaging tracers need to be tested for each disorder to see if they are useful for diagnosis, or for distinguishing between disorders.
The AFTD is dedicated to advancing biomarkers for diagnosis, The AFTD funds biomarker research, with a dedicated Biomarkers Initiative which awarded ~$5 million from 2016-2021, and a new Biomarkers Initiative starting in 2025.
Flortaucipir binds to a form of tau common in neurodegenerative diseases; by binding, the slight radiation of the tracer makes these accumulations visible to a PET scanner. While tau accumulations detected in some brain regions can contribute to a diagnosis, the lack of tau can contribute to a differential diagnosis by ruling out tauopathies. However, scientists are still uncertain if flortaucipir binding can accurately indicate the presence of tau tangles.
“We need to be cautious when using these molecular PET scans to determine eligibility for treatment, especially if treatment aims to target early stages of the disease,” lead author Keith Josephs, MD, told AlzForum.
The study by Josephs and researchers from Mayo Clinic is the largest yet to combine data on flortaucipir in vivo (in a living person) and post-mortem. The study included 248 participants, including people with Alzheimer’s disease and primary age-related tauopathy (PART), as well as people without tauopathy to serve as controls.
To measure the sensitivity of flortaucipir, the researchers compared its binding to what is known as Braak staging, a clinical method used to classify the intensity of Alzheimer’s or Parkinson’s pathology. Braak staging uses numbers (one through six) to indicate where tau tangles have spread in the brain by looking at the tissue post-mortem. Higher numbers indicate advanced stages of disease.
According to the study results, flortaucipir was detected in people with tau protein tangles at Braak stages five and six but had a far weaker signal in stages four and below. Plaques made of the amyloid protein increased the flortaucipir signal in people at lower Braak stages. In general, flortaucipir was able to identify people with higher tau levels but not those with lower levels at earlier stages of Alzheimer’s. Writing to Alzforum, researcher Rik Ossenkoppele, Ph.D., noted, “The inability of flortaucipir to detect [PART] is a very important observation because the field has been misinformed by several in vivo PET studies that have used inappropriate thresholds (i.e., too low for tau PET and too high for amyloid PET) to suggest that flortaucipir can be used to detect PART in vivo.”
Crucially, flortaucipir failed to flag tangles in participants with PART, which typically has lower tau levels than Alzheimer’s. Writing to Alzforum, researcher Rik Ossenkoppele, Ph.D., noted, “The inability of flortaucipir to detect [PART] is a very important observation because the field has been misinformed by several in vivo PET studies that have used inappropriate thresholds (i.e., too low for tau PET and too high for amyloid PET) to suggest that flortaucipir can be used to detect PART in vivo.”
The authors also investigated whether flortaucipir could discriminate PART diagnoses from controls (no neurodegenerative disease) based on the tau signals from different brain regions. It was found that while the tracer had 80% sensitivity, meaning a low chance of false positives, it only had 60% specificity, indicating a significant chance of a false negative. Further, Flortaucipir did not reliably discriminate between people with Alzheimer’s and those with early progression Alzheimer’s disease, and the authors warned this could result in people with Alzheimer’s being misdiagnosed with PART.
Josephs told Alzforum that whether other tau-based PET tracers could outperform flortaucipir is unknown. “I am not aware of any other [beta] amyloid or tau tracers that have been shown to be more sensitive to lower levels of AD pathology using autopsy-confirmed data,” he said. “More sensitive PET tracers are clearly needed.”
Previous studies have suggested that flortaucipir also has limited sensitivity and specificity to tau-based forms of FTD. In a 2019 study led by UCSF, researchers evaluated the performance of the tracer in a cohort of 45 participants with various forms of FTD, including behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), CBS, PSP, and different FTD-causing gene mutations. The results of the PET scans from the FTD cohort were compared to a 53-person control group.
The study authors noted that the binding flortaucipir through the brain and the frequency matched the expected distribution in FTD disorders like nfvPPA, CBS, and a bvFTD subtype associated with tau. However, compared to the control participants, the researchers noticed a lack of significant flortaucipir binding and considerable overlap in binding patterns between participants with FTD and control participants. This suggests that flortaucipir was not able to reliably detect disease.
Researchers found that flortaucipir also has a low binding affinity to forms of tau not associated with Alzheimer’s disease and does not bind to TDP-43. However, positive signals in people whose FTD is TDP-43-based led the authors to question the tracer’s specificity.
Like Josephs, the authors of the 2019 study called for a more sensitive and specific tau tracer, though they also highlighted the potential applications of flortaucipir. When an FTD pathology can be confidently predicted based on presenting symptoms or the presence of an FTD-causing genetic mutation, the authors note that the tracer could be used to study how tau spreads in relation to the progression of symptoms.
While further studies are needed to assess the utility of flortaucipir for FTD better, researchers have demonstrated that the tracer has potential uses in studying FTD and as a differential diagnostic tool.
Are you interested in participating in a clinical trial like those mentioned above? AFTD’s Studies Seeking Participants page features trials actively recruiting people with FTD, care partners, and family members. The FTD Disorders Registry can help you keep apprised of upcoming studies and offers the chance to share your lived experience with scientists.
Join and learn from others who understand the FTD journey at this virtual AFTD Meet & Greet event for people in Montana, Wyoming, North Dakota, and South Dakota.
The event will take place from 11:00 a.m. to 12:00 p.m. MT on Saturday, January 25, 2025.
RSVP for this event by emailing event host Susan Meagher at [email protected]. To learn more, download the flyer.
AFTD is committed to ensuring Help & Hope delivers informative articles and practical resources to ease your family’s FTD journey.
Each year, we look back through our archives to see which features resonated most with you, and we share them again. To see more content, we encourage you to look through the Help & Hope archive on AFTD’s website.
Loss of empathy is a distressing symptom of FTD, causing individuals to become uncharacteristically indifferent towards others. But there are strategies family and friends can use to cope with this change.
Read the FTD loss of empathy post.
Viva and Bruce Boerschel, part-time care partners for their son, Bob, told AFTD about the Sunflower lanyard that signals the need for support and understanding for the challenges they face when away from home.
Read the Hidden Disabilities Sunflower post.
The economic burden of FTD can be extreme, but there are social security programs that can offer financial relief and medical benefits after a diagnosis. Learn how to access these programs.
Read the Social Security Benefits for FTD post.
Getting one’s driver’s license is a milestone that signals independence. AFTD Persons with FTD Advisory Council co-chair Kevin Rhodes offers advice about driving with an FTD diagnosis.
Read the driving and FTD post.
Whether it causes a fixation on sweets or simply triggers overeating, hyperorality can be an especially concerning FTD symptom. AFTD has developed a resource for care partners to learn more and find strategies for managing it.
Read the hyperorality post.
Roaming can be a symptom of FTD that presents as compulsively walking, biking, or driving the same route repeatedly. In this article, we explore ways to limit the incidence of roaming and manage its potential risks.
Read the roaming vs. wandering post.