A case study recently published in Neurology: Clinical Practice described a man aged 65 years who presented with behavioral variant frontotemporal degeneration (FTD) despite conflicting results of Florbetapir PET.
The patient presented at a local memory clinic with memory complaints. Clinical assessment found no abnormalities. 2 years later, he presented with social disinhibition, reduced empathy, poor judgment, hoarding, inattention, and emotional blunting, along with prominent difficulties in abstraction, set shifting, and sequencing.
He was diagnosed with behavioral variant FTD (bvFTD). Family history included his mother’s dying at age 97 years with symptoms of dementia.
Magnetic resonance imaging (MRI) showed right- more than left-sided temporal atrophy, bilateral frontal and milder parietal atrophy. Fluorodeoxyglucose (FDG)-PET demonstrated frontotemporal hypometabolism. He was homozygous for the APOE ε4 allele. However, Florbetapir PET revealed increased tracer binding in all cortical regions of a centiloid value of 74%. He died at an age of 74 years after developing grasp reflexes and Parkinsonism.
Autopsy showed coexistent TDP-43 type A and Alzheimer disease (AD) pathologies and cerebrovascular disease. The brain showed considerable atrophy, neuronal loss, and gliosis in the temporal neocortex and amygdala with less prominence in the frontal cortex.
The basal ganglia showed severe compromise of the perforating arteries with calcification and a few tau deposits. All neocortical regions and subcortical grey matter contained diffuse subpial and perivascular amyloid plaques. The occipital cortex showed a few cored plaques and severe amyloid angiopathy.
Tau-related pathology was severe in CA1 and CA2 sectors and entorhinal cortex; the neocortex showed only a few neuritic plaques with more prominent changes in the temporal and parietal lobes.
Abnormal TDP-43 deposits consisted of neuronal cytoplasmic inclusions and dystrophic neurites (DN), which showed similar density in the hippocampus (dentate gyrus) and amygdala while DN were more prominent in the temporal neocortex. TDP-43-related pathology was milder in the frontal neocortex. Pathological features were in keeping with FTLD-TDP type A, Braak neurofibrillary tangle stage 2, (0-6), CERAD neuritic plaque score B (sparse), Thal phase 5 (Aβ plaque score 0-5), and severe small vessel disease in the basal ganglia.
With amyloid-PET imaging becoming a standard clinical investigation, a diagnosis of bvFTD may change to AD when amyloid-PET is positive, and autopsies in these cases often support AD. However, there could be coexistent pathology or inaccuracy of scan reports. In patients with a clinical diagnosis of FTD who are APOE ε4 carriers, amyloid-PET scan is positive in 19% at age 60 and 43% at age 80.
The study researchers said the patient’s probability of having AD, given a positive amyloid-PET, low pre-PET clinical probability of AD, his age, and APOE ε4 positivity, is “only 0.2.” Although the finding of TDP-43 type A pathology suggests LATE-NC as a diagnosis, the patient’s clinical phenotype, age, brain MRI, FTD-PET, and distribution and severity of TDP-43 pathology continued to suggest FTLD.
The study researchers concluded that the case “emphasizes the importance of integrating clinical evaluation, patterns of brain atrophy and FDG-PET hypometabolism, potential genetic etiologies, [pretest] probability of amyloid positivity and variability of clinico-pathological relationships before final diagnosis.”
Langheinrich T, Kobylecki C, Jones M, et al. Amyloid-PET positive patient with bvFTD: wrong diagnosis, false positive scan, or co-pathology? Neurol Clin Prac. Published online January 25, 2021. doi:10.1212/CPJ.0000000000001049