Article In Brief
An international consortium of experts in behavioral-variant frontotemporal dementia reviewed available medical literature and developed, by consensus, recommendations to help distinguish the disorder from other psychiatric conditions.
Behavioral-variant frontotemporal dementia (bvFTD) is often hard to differentiate from psychiatric disorders, but now a team of researchers and clinicians from around the world have developed recommendations that could make a diagnosis of bvFTD more accurate.
An analysis of the tests currently used and the team's new recommendations appear in the March issue of the journal Brain.
Lead study author Simon Ducharme, MD, a neuropsychiatrist at McGill University Health Centre and the Montreal Neurological Institute in Canada, said FTD represents a large percentage of early-onset dementia, but many clinicians are still confused about how to separate these conditions.
An International Consortium
Three years ago, Dr. Ducharme met Yolande Pijnenburg, MD, a neurologist at the Amsterdam University Medical Center who was leading a study on late-onset frontal lobe diseases and had recruited patients with behavioral changes who developed bvFTD or psychiatric disorders. The scientists wanted to expand the research in this area.
They recruited 45 scientists and clinicians from 15 countries with expertise in neuropsychiatric aspects of bvFTD into the Neuropsychiatric International Consortium for Frontotemporal Dementia.
They scanned the literature, dividing it into different diagnostic tools: bvFTD history-taking, physical and neurological exams, clinical scales, neuropsychological assessments, social cognition tests, structural imaging, biomarkers, and genetic testing.
Subgroups of experts in each domain were asked to come up with evidence-based guidelines in these areas. They asked, for example: What is the minimal requirement for the investigation of bvFTD? What would be the optimal clinical recommendation? And what are the tests that require more research?
Following the literature review and the individual recommendations, they sent out surveys to the consortium members asking whether they agreed or disagreed with their colleagues, and why. Then, based on the data collected they developed a set of consensus recommendations.
The researchers provided advice through a diagnostic algorithm summarizing their clinical recommendations. The first steps in making an accurate diagnosis include collecting collateral information on all symptoms from several family members; screen with the Montreal Cognitive Assessment (MoCA) as it seems to be a better cognitive screening instrument than the Mini-Mental State Examination (MMSE) for bvFTD, Dr. Ducharme said.
The second step includes a multidisciplinary neuropsychiatric assessment that also includes a recommendation to include tests to assess social and cognitive areas through at least one formal assessment, primarily the Ekman 60 Faces Test or the Social Cognitive and Emotional Assessment (SEA).
Two Kinds of Mistakes
Dr. Ducharme said that they were seeing two kinds of mistakes in the diagnosis of bvFTD: “Patients do not get identified fast enough—it usually takes six to seven years to get an accurate diagnosis—and other patients were misdiagnosed as having FTD when in fact they had a treatable psychiatric condition.”
Many of the diagnostic mistakes occur early on when a loved one notices odd behavior or an unusual lack of motivation and consults with a primary care doctor, Dr. Ducharme said. The family may then be referred to a general adult psychiatrist or neurologist not familiar with bvFTD who concludes that it is a psychiatric disorder.
It could take many years before they are seen at a clinic specializing in Alzheimer's and early-onset dementias like bvFTD, he said. An accurate diagnosis finally arrives when the disease is more advanced and there is abundant evidence of dementia and scans show atrophy in key brain regions.
The Importance of Brain Imaging
The researchers also reviewed the effectiveness of different brain imaging scans and said that it is important to order a 3D-T1 brain MRI “with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available.”
They provided evidence that PET to measure brain glucose levels is useful as an adjunct test but warned that patients who do not have specific enough psychiatric conditions can have non-specific findings leading to erroneous diagnoses.
If a diagnosis is still uncertain after the second stage of testing the scientists now recommended considering an additional test for neurofilament light chain protein, or NfL which could help clinicians assess whether it is bvFTD or psychiatric conditions based on a series of recent publications.
NfL is a non-specific marker of neurodegeneration and is not increased in patients with psychiatric conditions but does increase in bvFTD.
“We framed this NfL test as a recommendation to consider, provided that local laboratories can develop reference values,” said Dr. Ducharme.
Finally, in terms of genetic testing, the group is recommending to “lower the threshold for genetic testing of the chromosome 9 open reading frame gene (C9orf72) and test it in all patients suspected of having bvFTD, given the significant percentage of mutations found in apparent sporadic cases.”
In the past, genetic testing was reserved for patients with a known family history of bvFTD or amyotrophic lateral sclerosis. Both conditions have been linked to copy number variations in the gene.
Other gene mutations that are less common in bvFTD include progranulin (GRN) and microtubule-associated protein tau (MAPT) and the scientists agree that all three gene mutations should be ordered if there is a known family history. As many as 30 to 50 percent of patients do have a positive family history. An autosomal dominant mode of inheritance is found in 10-27 percent of all FTD cases, the authors reported. Dr. Ducharme said that it is important to correctly identify patients with bvFTD so that families can be counseled on taking care of their loved ones.
For now, there are no treatments for FTD, but it is important to get the diagnosis right so that patients can be enrolled in future clinical trials. Of note, there are several molecules for genetic FTD that are being currently tested in phase 1-2 studies. Also, patients with psychiatric disease who are misdiagnosed as having FTD will lose out on treatments that do work for many of these conditions.
Dr. Pijnenburg said that while it is easier to differentiate FTD from Alzheimer's, “it is much harder to disentangle bvFTD from psychiatric disorders.” “We learned early on that you can't rely on symptomatic features or brain scans to make the right diagnosis. Even with our expertise in FTD, we were getting it wrong. We need a multi-disciplinary approach.”
“Dr. Ducharme's paper is an important step forward in bringing expert consensus on this challenging topic,” said Bradford Dickerson, MD, FAAN, director of the Frontotemporal Disorders Unit and staff behavioral neurologist at Massachusetts General Hospital.
“The field has been grappling for years with the challenge of differentiating patients with bvFTD due to FTLD [frontotemporal lobar degeneration] neuropathologic changes (what we think of as the major forms of the disease) from clinical syndromes that may mimic bvFTD in some ways but are not likely due to neurodegenerative neuropathologic changes.”
Sara Mitchell, MD, MPH, a staff neurologist and assistant professor of neurology at Sunnybrook Health Sciences Centre in Toronto, agrees. Her interests are in the interface of neurology and psychiatry and she said there is no other disease that best represents the fusion between the two areas of medicine like FTD.
“Patients have primary psychiatric manifestations but it is caused by an underlying neurodegenerative process. Because these symptoms are the first to emerge, many people are referred to psychiatry and are often misdiagnosed, and the right diagnosis could take years. But the opposite is also true—that psychiatric conditions can mimic bvFTD and patients can also be diagnosed with a neurodegenerative disease.
“These consensus guidelines are a good first step,” she said. “To have a panel of experts think about these issues is important. The algorithm they outline mirrors what happens in a specialty clinical setting. It is quite detailed and comprehensive and these recommendations add to the process and help pave the way forward. This is where we should focus our research efforts.”
“This paper is highly relevant, offering practical tools to the clinical field in the challenging differential diagnosis between bvFTD and primary psychiatric disorders,” added Welmoed Krudop, MD, PhD, a psychiatrist in training at the Amsterdam University Medical Center. She is a pioneer in the study of late life psychiatric conditions and bvFTD.
“The described multidisciplinary approach enables clinicians to apply these neurological as well as psychiatric recommendations, whereby taking into account both the risk for over-diagnosing as well as under-diagnosing bvFTD. For instance, by emphasising the low specificity of frontal hypometabolism on the FDG-PET for bvFTD, over-diagnosing may be reduced. They also described the various psychiatric manifestations and slow rate of progression in some bvFTD cases, like the C9orf72 repeat expansion carriers, and this may help clinicians to reduce the chance of missing a bvFTD diagnosis.”
Testing all suspected bvFTD cases for C9orf, since C9orf-cases are heterogeneous and may be atypical, is therefore an effective recommendation with a clear rationale, she added.
“Even though many psychiatric disorders like schizophrenia, bipolar disease, or autism spectrum disorder, also show social cognitive impairments, the deficits in bvFTD are usually more profound and such a test is easily added to the usual neuropsychological test battery,” she explained. “Disease insight is usually absent in bvFTD.”