How Redefining The Diagnostic Odyssey Can Lead To Better Patient Outcomes

By Wendy Cogan, patient advocate

I’m a nurse, a wife, and now a widow. I learned the hard way that even with world-class specialists and the newest tests, the right diagnosis can arrive too late. For years, my husband Jeff and I navigated labels that shifted as his symptoms evolved and biomarkers conflicted. Jeff remained sharp in conversation while his day-to-day function plummeted. The truth came after he died when a letter arrived with a pathology different from the one that had guided our path during Jeff’s life. This piece is about turning his diagnostic odyssey into practical guidance for clinical leaders so more patients land in the right trials with fewer detours.

Jeff loved boating and was an avid swimmer. He was extremely bright, strategic, and carried a vocabulary that made me pause in admiration. He was a visual savant with a joyous laugh. His quick wit and intelligence brought him many successes, including helping a cancer center achieve National Cancer Institute designation, which fostered clinical trials. He greatly valued the importance of research.

Neurodegenerative diseases are among medicine’s toughest puzzles, where clinical symptoms overlap, conditions may morph significantly, and biomarker science is evolving fast. Trial success depends on enrolling participants whose underlying pathology truly matches the drug’s mechanism, requiring clinicians to piece together evidence from a variety of sources. Biomarkers, genetics, imaging, and AI can offer breakthroughs, but they must be paired with caregiver insight and post-mortem validation to ensure correct pathology for trial enrollment.

To transform the diagnostic odyssey, we must first confront the complexity of diagnosis to understand why even the best tools and brightest minds are often insufficient.

Learnings From Jeff’s Diagnostic Odyssey

Jeff’s story is just one example of how confusing, conflicting, and maddening the diagnostic odyssey can be.

Initially, Jeff developed severe depression that evolved into bipolar disorder at age 63. In 2016, he started a highly uncharacteristic buying spree of cars, boats, and houses. He underwent 14 rounds of ECT in 2018, lost his memory of driving rules, and totaled his car. Later, we learned this was the prodromal stage of his dementia and not a psychiatric illness. Clinicians need to be aware that late age onset psychiatric symptoms can be early red flags for dementia, so patients can join clinical trials earlier.

Top centers first diagnosed Jeff with Lewy body disease (LBD) in 2020. In 2021, when Jeff’s apraxia progressed, they weighed corticobasal syndrome (CBS) caused by LBD pathology (misfolded alpha-synuclein), against CBS caused by corticobasal degeneration (CBD) pathology (4R tau). Jeff’s SAAmplify-αsyn CSF test for the alpha-synuclein biomarker was negative for LBD, but later the Syn-One α-syn skin biopsy was positive for LBD. His FDG-PET and tau PET pointed more toward LBD. CSF tests and amyloid scans remained negative for Alzheimer’s. Despite a strong family history of dementia and ALS, genetic testing was negative, but not all mutations have been discovered yet.

Later came Jeff’s inability to tie his shoes, which evolved into the need for help with all his activities of daily living. He didn’t know where objects or his body were located in space. Eventually, he didn’t know if he was walking or sitting. His hand acted like it had a mind of its own and clamped onto his body without letting go (alien limb). His OCD became so profound that he was flushing the toilet hundreds of times a day.

Finally, after Jeff died, the autopsy gave us an official diagnosis of frontotemporal lobar degeneration (FTLD)-tau CBD with no Lewy body or Alzheimer’s pathology, clarifying that the positive LBD signal from the skin biopsy test was a false lead for the pathology in Jeff’s brain.

For clinical trials, these challenges directly impact who gets enrolled and whether therapies are tested against the right disease. Studies need built-in safeguards. When a therapy is designed to target a specific pathology, enrollment should be backed up by more than one type of test and the most accurate biomarkers, especially in complex cases, like Jeff’s.

The Complexity Of Diagnosis

Reaching a clear diagnosis in neurodegenerative disease is rarely straightforward. Even at leading medical centers, clinicians must piece together clues from exams, neuropsychiatric testing, genetic testing, PET scans, fluid biomarkers like CSF or plasma proteins, and sometimes even newer peripheral assays and evolving scan ligands. Despite these advances, accuracy remains difficult to achieve for three major reasons.

First, mixed pathology is more common than not. Data from the Rush Memory and Aging Project found that 78% of participants with at least one type of dementia-related brain change had two or more, and 58% had three or more. The challenge is not just naming the diseases present, but identifying which pathology is truly driving the brain dysfunction most relevant to clinical trials. In Jeff’s case, he had conflicting biomarkers confusing his diagnosis. We didn’t know if he had mixed pathology with one type in his periphery and a different type in his brain or just one pathology.

Second, many patients live with symptoms that are similar across different types of dementia. Conditions such as CBD and LBD can cause visuospatial challenges, executive functioning issues, Parkinsonism, and similar behavioral and psychiatric features.

Third, biomarker science is always evolving. Novel tools hold great promise, but their true accuracy can only be established through validation against autopsy data. Neurologist expertise alone cannot reliably predict how well these biomarkers perform across different conditions and disease stages. Early reports of sensitivity and specificity, often based on consensus clinical cohorts, frequently shift as larger post-mortem series are studied. Until more of these validation studies are available, any single test result should be seen as one piece of a larger puzzle rather than a final answer.

The Caregiver As A Critical Source Of Clinical Evidence

Caregivers are often the most consistent observers of change. They notice fluctuations across settings and pick up on details that clinic visits can miss. Whether it’s difficulty with daily tasks or early behavioral changes, these observations provide valuable evidence that can strengthen diagnosis and improve trial selection.

Often, caregivers will conduct their own research. Noticing Jeff’s continued decline in 2019, I used my nursing knowledge to dig deep into the science by watching dementia webinars. I studied diagnostic criteria and initially suspected a type of FTLD called behavioral variant frontotemporal dementia (bvFTD) with evolving motor symptoms, or maybe LBD. I reached out to neurologists for confirmation and scans. The FDG-PET results showed FTD was unlikely. However, Jeff did not have hallucinations, REM sleep behavior disorder, or dysautonomia often associated with LBD. Based upon the initial scans, the neurologist suspected LBD or atypical Alzheimer’s, but said we would not know which one for several years.

When the α-SYN CSF test was negative for LBD, CBD was suspected. I flagged potential CBD-frontal behavioral-spatial syndrome (FBS), a clinical presentation of CBD that is associated with visuospatial issues, executive dysfunction, and behavioral or psychiatric issues. FBS psychiatric issues can mimic bvFTD.

However, later, when Jeff’s skin test was positive for LBD, a top neurologist leaned more toward LBD pathology based upon the skin test and Jeff’s FDG PET and tau PET patterns. At that time, he thought the positive LBD skin test was more accurate than the negative CSF test. Now, years later, extensive autopsy results have confirmed that the SAAmplify-αSYN test accuracy is now autopsy confirmed. If we had known this then, Jeff’s whole story would have unfolded differently.

In 2023, I feared Jeff’s longevity was limited due to his rapidly declining symptoms. The FDG-PET showed mild progression, so one neurologist said Jeff could live five more years. Another neurologist flagged that Jeff was at significant risk of dying from a fall and that scans should not be used to predict longevity. This proved correct, and Jeff died after falling down the stairs in 2024, almost four and a half years after his LBD diagnosis.

Jeff’s autopsy results showed FTLD-CBD, 4R tau, and the neurologists agreed Jeff had the FBS subtype. Despite the mild FDG-PET progression, Jeff’s CBD pathology was significant. The report said they were amazed Jeff survived as long as he did.

My instincts were often correct, but also thrown off by conflicting tests. Caregiver insights don’t replace biomarkers or scans, but they give them context, helping clinicians see red flags sooner and make better decisions about who belongs in which trial.

I greatly appreciated the dedication and support of Jeff’s neurologists, who, despite the uncertainty, partnered well with me to ensure Jeff had excellent tests and care. Also, I heavily leveraged resources from CurePSP, AFTD, and LBDA.

Gathering Stronger Trial Data

Misdiagnosis doesn’t just skew data—it can inaccurately predict progression and close the door on therapies and drug trials that might have made a difference. It burdens patients and families with unsuccessful trials while muddying the results scientists are working so hard to measure.

To avoid this, trial design must demand stronger evidence. Caregiver input should be built into protocols. Biomarkers should be validated before they are used to decide eligibility, so only the right patients are included. Autopsy programs should be funded and linked to trials, so what’s learned at the end of life improves accuracy for the next generation. Caregiver-reported symptoms and outcomes should also feed real-world evidence, adding depth to the full clinical picture.

Our journey illustrates how eligibility can go wrong if early biomarkers aren’t confirmed. Jeff’s CSF alpha-synuclein test was negative for LBD, but a later skin biopsy was positive and, at the time, was considered more convincing. Throughout, Alzheimer’s markers stayed negative. The working diagnoses shifted (probable LBD, then a CBS/LBD mix) until autopsy clarified CBD (FTLD-tau) with no LBD or AD. If we had used only the skin test to steer a Lewy body trial, Jeff would have been the wrong patient for the wrong mechanism. Trials need more than one kind of evidence, and to focus on which pathology is driving the brain dysfunction being treated by the clinical trial.

Together, these steps raise the bar for enrollment, reduce harm, and make each trial a more reliable test of whether a treatment truly works.

Building A Smarter Diagnostic Ecosystem

Transforming the diagnostic odyssey will not come from a single breakthrough but from a collection of science-driven insights. A modern, trial-ready system should combine caregiver and patient observations captured in consistent formats; evolving imaging interpreted in light of the full clinical picture; and biomarker panels whose accuracy is tracked over time and confirmed through autopsy. AI tools and algorithms can bring these pieces together and predict the most likely disease course when data are viewed in totality. Clear diagnostic pathways make the process more reliable across trials.

But tools alone won’t solve the problem. Real progress requires strong partnerships across the ecosystem of caregivers who contribute lived insight, neurologists who guide diagnosis, researchers and trial designers who build protocols, and payers and advocacy networks who help connect patients to care and research opportunities. Everyone needs a seat at the table. This level of integration is essential for accelerating learning by linking what we see during life with what is confirmed after death.

Mapping The Path Forward

Not every patient will live to benefit from the therapies they help make possible. Jeff didn’t. But his journey can strengthen the path for those who come next. If we capture conditions more accurately, require the most accurate forms of evidence before enrollment, and validate emerging biomarker tests against autopsy, each trial can become a stronger tool for discovery rather than a gamble.

Jeff’s autopsy didn’t rewrite his story, but it taught us how to read it. As we continue to gather and grow our knowledge of devastating neurodegenerative diseases, the goal isn’t simply to shorten the diagnostic odyssey but to better map it so patients and caregivers can navigate it with more clarity and greater confidence in the science guiding their care. Central to this work is elevating caregiver data from anecdote to evidence and expanding the database of autopsy-confirmed cases to anchor future progress.

In 2025, Jeff’s case was presented during the International Lewy Body Dementia Conference to neurologists from around the world. Jeff would have been so proud to know he is helping to build a future where more families have a fair shot at the right science.  

About The Author:

Wendy Cogan worked as a registered nurse and then as a telecommunications executive. Her medical advocacy role began when, after extensive research, she suspected she had Ehlers-Danlos syndrome (EDS), an underdiagnosed connective tissues disease. She went to Mayo where she received her EDS diagnosis. She established an EDS charity, hosted an educational seminar, contributed to publications, and helped established a pediatric EDS clinic. These experiences gave her the tools to research her husband, Jeff’s, corticobasal degeneration (CBD), a motor variant of frontotemporal dementia (FTD). Wendy was Jeff’s sole caregiver and fiercely advocated for his diagnosis and care while he battled his illness for many years. To honor his wishes to support dementia research, she enrolled Jeff in the LBD Longitudinal Imaging Biomarkers study and donated his brain to science. She lives in Kansas City, Missouri, and continues to advocate for improved diagnosis, research, and treatment for EDS and CBD.