From clinical phenotype to proteinopathy: molecular neuroimaging in neurodegenerative dementias

Abstract

Neurodegenerative dementias are characterized by the abnormal accumulation of misfolded proteins. However, its diagnostic criteria are still based on the clinical phenotype. The development of biomarkers allowed in vivo detection of pathophysiological processes. This article aims to make a non-systematic review of the use of molecular neuroimaging as a biomarker. Molecular neuroimaging is based on the use of radiotracers for image acquisition. The radiotracer most used in PET is 18F-fluorodeoxyglucose (FDG), with which it is possible to study the regional brain glucose metabolism. The pattern of regional hypometabolism provides neuroanatomical information on the neurodegenerative process, which, in turn, has a good specificity for each type of proteinopathy. FDG is very useful in the differential diagnosis of neurodegenerative dementias through the regional pattern of involvement, including dementia with Lewy bodies and the spectrum of frontotemporal dementia. More recently, radiotracers with specific ligands to some of the pathological proteins have been developed. Pittsburgh compound B (PIB) labeled with 11C and the ligands that use 18F (florbetapir, florbetaben and flutemetamol) are the most used radiotracers for the detection of insoluble β-amyloid peptide in Alzheimer's disease (AD). A first generation of ligands for tau protein has been developed, but it has some affinity for other non-tau protein aggregates. A second generation has the advantage of having a higher affinity for hyperphosphorylated tau protein, including in primary tauopathies.

Figure 1.. Summary of the molecular imaging findings in the different neurodegenerative diseases. First line: spectrum of proteinopathies causing neurodegenerative dementias and their respective clinical phenotypes. Pathological proteins: TDP-43, FUS, Tau, beta-amyloid, and alpha-synuclein. Second line: Patterns of regional glucose hypometabolism on brain FDG-PET that suggest or support each proteinopathy.;Third line: Patterns of amyloid PET with ¹¹C-PIB in each condition. Fourth line: Patterns of uptake in dopamine transporter (DAT) SPECT or PET tracers or ¹⁸F-Fluordopa PET (SPECT images with ^99mTc-TRODAT). Fifth line: Patterns of uptake in cardiothoracic ¹²³I-mIBG scintigraphy, a tracer of the sympathetic innervation. The white arrow in the first image on the left, third line indicates hypometabolism in the left motor cortex in motor neuron disease (ALS/Mills Syndrome); yellow arrows in the last images on the right, third line: hypometabolism in both putamen and the cerebellum seen in MSA. Orange arrow in the last image on the right in the fifth line: absence of myocardial uptake of ¹²³I-mIBG seen in synucleinopathies.

Figure 2.. Flowchart showing a proposal in the sequence of the request of molecular neuroimaging in the diagnostic investigation of cognitive and/or behavioral decline in the clinical practice. Abbreviations: FTD: frontotemporal dementia; AD: Alzheimer's disease; DLB: dementia with Lewy bodies.; PET: Positron Emission Tomography; SPECT: single photon emission tomography; FDG: ¹⁸F-Fluorodeoxyglucose; DAT: dopamine transporter; ¹²³I-mIBG: iodine-123-labeled meta-iodo-benzyl-guanidine; CSF: cerebrospinal fluid; MRI: magnetic resonance imaging; CT: computed tomography.