Longitudinal Amyloid-β PET in Atypical Alzheimer’s Disease and Frontotemporal Lobar Degeneration

Abstract

Background: Rates of beta-amyloid (Aβ) accumulation have been characterized across the cognitively normal to typical Alzheimer's dementia spectrum, but little is known about Aβ accumulation in atypical Alzheimer's disease (AD) and other neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD). We aimed to characterize longitudinal Aβ accumulation, and determine the influence of age, apolipoprotein E genotype, disease duration, and sex in atypical AD and FTLD. Methods: 322 patients (138 atypical AD, 184 FTLD) underwent Pittsburgh compound B PET scanning, with 73 having serial PiB-PET scans (42 atypical AD, 31 FTLD). Global Aβ standard uptake value ratios were calculated for every scan. Mixed effects models were used to assess the effect of age, APOE genotype, disease duration, and sex on baseline and change measures of Aβ. Results: Atypical AD showed higher baseline Aβ than FTLD. Rate of Aβ accumulation was not associated with baseline Aβ in either group. Older age was associated with greater baseline Aβ and faster rates of accumulation in FTLD. In patients under age 70, atypical AD showed faster rates of accumulation than FTLD. APOE e4 genotype was associated with greater baseline Aβ in FTLD but did not influence rates of accumulation. Rates of Aβ accumulation were faster in FTLD patents with time from onset-to-PET ≤4 years. Female sex was associated with faster rates of accumulation in atypical AD.

Imaging Techniques in Alzheimer’s Disease: A Review of Applications in Early Diagnosis and Longitudinal Monitoring

“…This difference suggested a temporal lag between tau deposition and the progression of neurodegeneration. This assumption has been previously proposed by other studies as well [ 114 , 115 ]. Furthermore, the research found that age has a negative effect on disease progression, since younger patients had higher rates of tau accumulation and atrophy.…”

“…There is an urgent need for a tool to discover even the smallest Aβ deposits, and cut-off levels need to be defined in order to make studies comparable [ 4 ]. Furthermore, most studies have used radiolabeled tracers in the typical form of the AD spectrum, resulting in much knowledge about Aβ accumulation in typical AD, while the atypical, non-amnestic type has remained understudied [ 115 ]. An increasing body of evidence suggests the utility of Aβ-PET to diagnose patients with atypical manifestations of AD, such as posterior cortical atrophy (PCA) and logopenic-variant primary progressive aphasia (LvPPA) [ 104 , 116 ].…”

Ex vivo MRI and histopathology detect novel iron-rich cortical inflammation in frontotemporal lobar degeneration with tau versus TDP-43 pathology

“…( Irwin et al, 2015 ) Indeed, while some frontotemporal dementia (FTD) clinical syndromes have group-level statistical associations with one of these proteinopathies, the majority of FTD syndromes do not reliably predict pathology. ( Irwin et al, 2015 , Gorno-Tempini et al, 2011 , Höglinger et al, 2017 , Giannini et al, 2019 , Irwin et al, 2018 , Perry et al, 2017 , Spinelli et al, 2017 ) Moreover, while various degenerative processes can be detected using structural, ( McKiernan and O’Brien, 2017 , McMillan et al, 2014 , Rohrer et al, 2009 , Whitwell et al, 2005 , Whitwell et al, 2015 , Perry et al, 2017 ), diffusion, ( McMillan et al, 2014 , Whitwell et al, 2010 , Illán-Gala et al, 2019 ), and spectroscopic MRI, ( Maul et al, 2020 , Murley et al, 20202020 ), as well as PET, ( Kim et al, 2019 , Whitwell et al, 2020 ); there is currently no method to directly sensitize traditional MRI, or any other in vivo imaging technology, including molecular imaging, to the specific protein inclusions or pathological features that would allow in vivo discrimination of patients with tau and/or TDP-43 inclusions in FTLD. In this report, we explore the novel combination of histopathology and T 2 *-weighted (T2*w) ex vivo 7 T MRI for the purpose of developing a more reliable, data-driven approach to diagnosis of pathology in FTLD spectrum disorders.…”

Synergistic Association between Plasma Aβ1–42 and p-tau in Alzheimer’s Disease but Not in Parkinson’s Disease or Frontotemporal Dementia

“…A recent study assessing Aβ in 98 individuals with pathologically confirmed frontotemporal dementia syndromes showed that in individuals with various types of frontotemporal dementias, 8%–29% of individuals showed Aβ deposition in the frontotemporal cortexes, and the prevalence increased to 29%–50% if the basal ganglia or substantia nigra were included . Amyloid molecular imaging studies using Pittsburgh Compound B (PiB)-PET scans also revealed amyloid depositions in cortexes and subcortical areas in individuals with FTD. , The coexistence of Aβ and p-tau or other proteinopathies in FTD syndrome, such as TDP-43, fused in sarcoma can be expected; thus, it is unsurprising to observe elevated plasma Aβ 1–42 levels in individuals with FTD. The mean level of plasma Aβ 1–42 is approximately at the level of MCI due to the AD in this study.…”