In a small percentage of people with Alzheimer’s disease, behavioral changes early on—such as a disregard for social norms or loss of empathy—can lead physicians to mistakenly diagnose behavioral variant frontotemporal dementia (bvFTD). How can they better distinguish this variant of AD? A paper posted September 20 on medRχiv suggests that metabolic patterns are key. Scientists led by Ellen Singleton and Rik Ossenkoppele at Amsterdam University Medical Center found regions of hypometabolism that may explain the clinical phenotype. The results have implications for clinical diagnosis, while at the same time offering a better scientific grasp of the mechanisms underlying this atypical Alzheimer’s.
- Brain scans reveal metabolic contributors to behavioral subtype of AD.
- Hypometabolism in frontal regions distinguishes bvAD from typical AD.
- Both bvAD and bvFTD share hypometabolism in the anterior default mode network.
“This is the first study focused on bvAD to show such a diversity of neuroimaging features,” Singleton told Alzforum. “It suggests FDG-PET is more accurate in differentiating these diseases than MRI.” In a previous structural MRI study, Ossenkoppele and colleagues had expected to find frontal cortical atrophy in people with bvAD, but were puzzled to find none (Jul 2015 news). Now, in an extension of that study, the scientists report FDG PET imaging data for some of the same participants. They also asked if subcortical atrophy or white-matter lesions in areas that connect to frontal areas of the brain might account for the behavioral symptoms of bvAD.
Singleton and colleagues examined both MRI and FDG-PET scans from 150 people recruited from the University of California, San Francisco, and the University of Berkeley. Twenty-nine had been diagnosed with bvAD, 28 with typical AD, 28 with bvFTD, and 65 were cognitively normal controls.
Frontal Hypometabolism. On FDG PET scans, hypometabolism in frontal areas distinguishes bvAD from typical AD, and matches areas of hypometabolism in bvFTD. [Courtesy of Singleton et al., 2019.]
On the FDG-PET scans, they found a pattern among bvAD patients that largely matched patients with typical AD—hypometabolism in the posterior cingulate cortex, precuneus, and lateral temporoparietal regions. In addition, the bvAD patients had subtle metabolic deficits in the frontoinsular regions, including the right lateral frontal lobe and bilateral insulae, that did not appear in typical AD (see image above). This anterior pattern more closely resembled that seen in scans of bvFTD patients.
The researchers also measured FDG uptake across brain networks, to look for metabolic connectivity changes. Uptake in the posterior default mode network (DMN) was lower in both bvAD and typical AD patients than in controls, suggesting these areas were affected in both types of AD. However, less uptake across the anterior DMN distinguished bvAD from typical AD, and matched the pattern seen in bvFTD.
The researchers found no differences in subcortical atrophy or white-matter damage between typical and bvAD.
Together, the data suggest that common metabolic and connectivity deficits underlie the behavioral phenotype shared among bvAD and bvFTD patients. It is unclear why frontal areas are less active in this subset of AD patients. Ossenkoppele and colleagues are examining PET tau scans of people in this cohort to see if the pattern of tau tangles in the brain is also different.
Aside from helping explain the etiology of bvAD, the findings will help in differential diagnosis, Ossenkoppele told Alzforum. He has reported that up to 40 percent of patients diagnosed with bvFTD were found at autopsy to have had bvAD instead (Ossenkoppele et al., 2012; Forman et al., 2006). They may have missed out on medications such as acetylcholinesterase inhibitors or memantine that could have alleviated their symptoms. Conversely, treating misdiagnosed bvFTD patients with AD medications can worsen behavioral symptoms. “It is critically important to diagnose correctly, even though disease-modifying treatments are not available,” said Ossenkoppele.
“It’s clear that the presence of behavioral/frontal features in a person with an amnestic disorder should not lead to the diagnosis of AD being discarded,” wrote Michael Woodward, Heidelberg Repatriation Hospital, Australia, to Alzforum. “In the future, [better diagnosis] will impact on matching disease modifying treatments to the patient, and even now may impact recruitment into trials.”
“Ultimately when clinicians have better tools and knowledge to diagnose this patient group, they can work toward better prognosis and patient management, as well as a better understanding of individual patients’ disease,” Singleton added.—Gwyneth Dickey Zakaib
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- Forman MS, Farmer J, Johnson JK, Clark CM, Arnold SE, Coslett HB, Chatterjee A, Hurtig HI, Karlawish JH, Rosen HJ, Van Deerlin V, Lee VM, Miller BL, Trojanowski JQ, Grossman M. Frontotemporal dementia: clinicopathological correlations. Ann Neurol. 2006 Jun;59(6):952-62. PubMed.
- Monacelli F, Martella L, Parodi MN, Odetti P, Fanelli F, Tabaton M. Frontal Variant of Alzheimer's Disease: A Report of a Novel PSEN1 Mutation. J Alzheimers Dis. 2019;70(1):11-15. PubMed.
- Singleton EH, Pijnenburg YA, Sudre CH, Groot C, Kochova E, Barkhof F, La Joie R, Rosen HJ, Seeley WW, Miller B, Cardoso MJ, Papma J, Scheltens P, Rabinovici GD, Ossenkoppele R. Investigating the clinico-anatomical dissociation in the behavioral variant of Alzheimer's disease. medRχiv September 20, 2019