Association of short-term cognitive decline and MCI-to-AD dementia conversion with CSF, MRI, amyloid- and 18F-FDG-PET imaging

Abstract

Disease-modifying treatment trials are increasingly advanced to the prodromal or preclinical phase of Alzheimer's disease (AD), and inclusion criteria are based on biomarkers rather than clinical symptoms. Therefore, it is of great interest to determine which biomarkers should be combined to accurately predict conversion from mild cognitive impairment (MCI) to AD dementia. However, up to date, only few studies performed a complete A/T/N subject characterization using each of the CSF and imaging markers, or they only investigated long-term (≥ 2 years) prognosis. This study aimed to investigate the association between cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), amyloid- and 18 F-FDG positron emission tomography (PET) measures at baseline, in relation to cognitive changes and conversion to AD dementia over a short-term (12-month) period. We included 13 healthy controls, 49 MCI and 16 AD dementia patients with a clinical-based diagnosis and a complete A/T/N characterization at baseline. Global cortical amyloid-β (Aβ) burden was quantified using the 18 F-AV45 standardized uptake value ratio (SUVR) with two different reference regions (cerebellar grey and subcortical white matter), whereas metabolism was assessed based on 18 F-FDG SUVR. CSF measures included Aβ 1–42 , Aβ 1–40 , T-tau, P-tau 181 , and their ratios, and MRI markers included hippocampal volumes (HV), white matter hyperintensities, and cortical grey matter volumes. Cognitive functioning was measured by MMSE and RBANS index scores. All statistical analyses were corrected for age, sex, education, and APOE ε4 genotype. As a result, faster cognitive decline was most strongly associated with hypometabolism (posterior cingulate) and smaller hippocampal volume (e.g., Δstory recall: β = +0.43 [ p < 0.001] and + 0.37 [ p = 0.005], resp.) at baseline. In addition, faster cognitive decline was significantly associated with higher baseline Aβ burden only if SUVR was referenced to the subcortical white matter (e.g., Δstory recall: β = −0.28 [ p = 0.020]). Patients with MCI converted to AD dementia at an annual rate of 31%, which could be best predicted by combining neuropsychological testing (visuospatial construction skills) with either MRI-based HV or 18 F-FDG-PET. Combining all three markers resulted in 96% specificity and 92% sensitivity. Neither amyloid-PET nor CSF biomarkers could discriminate short-term converters from non-converters.

The Power of EEG to Predict Conversion from Mild Cognitive Impairment and Subjective Cognitive Decline to Dementia

“…The use of various MRI and PET methods and cerebrospinal fluid (CSF) examination, measuring concentrations of amyloidβ, phosphorylated and total tau proteins, as well as other proteins, including inflam matory markers, have shown to be helpful in predicting patients with MCI and SCD who will convert to demen tia, especially to AD [16][17][18][19][20][21][22]. A recent Cochrane review, however, does not support the use of βamyloid PET as biomarker for AD, but studies examining the combina tion of cognitive tests with CSF proteins, MRI, and FDGPET have shown excellent results in identifying people with MCI that would convert to dementia [23][24][25]. However, the use of biomarkers are time and per sonnel consuming, costly, and some of them are inva sive, and, consequently, not ideal for use in daily clinical practice, except in subspecialized settings.…”

Discordant Alzheimer's neurodegenerative biomarkers and their clinical outcomes in older adults without dementia

“…Previous studies have reported the correlations between neuronal injury factors, and it has been noted that the combination of these biomarkers might provide better prediction than either source of data alone [15,19,21,22]. Vos et al also suggested that individuals with both CSF Aβ deposition and neuronal injury showed an increased risk of disease progression [16].…”

“…Discordant biomarkers potentially have signi cant implications for neurobiological mechanisms of biomarker discrepancies and AD neuropathogenesis [17]. Prior studies mainly focused on the associations of neurodegenerative biomarkers or only a single biomarker rather than investigation into the combination of multiple neurodegenerative markers utilizing various modalities [18][19][20][21][22]. However, whether and how "N" biomarker discordance affects clinical outcomes is currently understudied.…”

Discordant Alzheimer's neurodegenerative biomarkers and their clinical outcomes in older adults without dementia

“…Previous studies have reported the correlations between neuronal injury factors, and it has been noted that the combination of these biomarkers might provide better prediction than either source of data alone [15,19,21,22]. Vos et al also suggested that individuals with both CSF Aβ deposition and neuronal injury showed an increased risk of disease progression [16].…”

“…Discordant biomarkers potentially have signi cant implications for neurobiological mechanisms of biomarker discrepancies and AD neuropathogenesis [17]. Prior studies mainly focused on the associations of neurodegenerative biomarkers or only a single biomarker rather than investigation into the combination of multiple neurodegenerative markers utilizing various modalities [18][19][20][21][22]. However, whether and how "N" biomarker discordance affects clinical outcomes is currently understudied.…”