Date Published: April 25, 2018
Publisher: BioMed Central
Author(s): Chiara Cerami, Alessandra Dodich, Sandro Iannaccone, Giuseppe Magnani, Roberto Santangelo, Luca Presotto, Alessandra Marcone, Luigi Gianolli, Stefano F. Cappa, Daniela Perani.
Mild cognitive impairment (MCI) is a heterogeneous syndrome resulting from Alzheimer’s disease (AD) as well as to non-AD and non-neurodegenerative conditions. A subset of patients with amnestic MCI (aMCI) present with an unusually long-lasting course, a slow rate of clinical neuropsychological progression, and evidence of focal involvement of medial temporal lobe structures. In the present study, we explored positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers in a sample of subjects with aMCI with such clinical features in order to provide in vivo evidence to improve disease characterisation in this subgroup.
Thirty consecutive subjects with aMCI who had long-lasting memory impairment (more than 4 years from symptom onset) and a very slow rate of cognitive progression were included. All subjects underwent fluorodeoxyglucose-positron emission tomography (FDG-PET) metabolic imaging. A measure of cerebral amyloid load, by PET and/or CSF, was obtained in 26 of 30 subjects. The mean clinical follow-up was 58.3 ± 10.1 months.
No patient progressed to dementia during the follow-up. The typical AD FDG-PET pattern of temporoparietal hypometabolism was not present in any of the subjects. In contrast, a selective medial temporal lobe hypometabolism was present in all subjects, with an extension to frontolimbic regions in some subjects. PET imaging showed absent or low amyloid load in the majority of samples. The values were well below those reported in prodromal AD, and they were slightly elevated in only two subjects, consistent with the CSF β-amyloid (1–42) protein values. Notably, no amyloid load was present in the hippocampal structures.
FDG-PET and amyloid-PET together with CSF findings questioned AD pathology as a unique neuropathological substrate in this aMCI subgroup with long-lasting disease course. The possibility of alternative pathological conditions, such as argyrophilic grain disease, primary age-related tauopathy or age-related TDP-43 proteinopathy, known to spread throughout the medial temporal lobe and limbic system structures should be considered in these patients with MCI.
Mild cognitive impairment (MCI) is a heterogeneous syndrome that can be due to Alzheimer’s disease (AD) and non-AD pathologies . The presence of an early and significant objective deficit of episodic memory is considered the main criterion supporting the diagnosis of typical AD and the best cognitive predictor of the development of AD dementia [2, 3]. Though the amnestic syndrome of hippocampal type is the most typical presentation in prodromal AD, impairments in delayed recall tasks may be present in individuals with non-AD disorders, such as the behavioural variant of frontotemporal dementia (bvFTD) , argyrophilic grain disease (AGD) [5, 6] and the recently identified suspected non-AD pathology (SNAP) [7–9].
Our sample of subjects with aMCI with prevalent or exclusive long-term memory deficits and a slow cognitive progression did not show the FDG-PET hypometabolism pattern typical of AD. They had reduced glucose metabolism in the medial temporal lobe structures with no amyloid load visualised by PET imaging in these structures (see Figs. 1 and 2).
The main contribution of the present in vivo combined biomarker study (FDG-PET for neurodegeneration and amyloid-PET and CSF for pathology) is that additional nosographic classifications besides the limbic AD variant need to be considered in patients with MCI with a long-lasting disease course and slowly progressing or non-progressing cognitive decline.