Association of Cognitive Impairment With Free Water in the Nucleus Basalis of Meynert and Locus Coeruleus to Transentorhinal Cortex Tract

Objective:Determine the relationship between diffusion microstructure and early changes in Alzheimer’s disease (AD) severity as assessed by clinical diagnosis, cognitive performance, dementia severity, and plasma concentrations of neurofilament light chain.Methods:Diffusion MRI scans were collected on cognitively normal participants (CN), patients with early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and AD. Free water (FW) and FW-corrected fractional anisotropy were calculated in the locus coeruleus to transentorhinal cortex tract, four magnocellular regions of the basal forebrain (e.g. nucleus basalis of Meynert), entorhinal cortex, and hippocampus. All patients underwent a battery of cognitive assessments; neurofilament light chain levels were measured in plasma samples.Results:FW was significantly higher in EMCI compared to CN in the locus coeruleus to transentorhinal cortex tract, nucleus basalis of Meynert, and hippocampus (mean Cohen d = 0.54; pfdr<0.05). FW was significantly higher in AD compared to CN in all the examined regions (mean Cohen d = 1.41; pfdr<0.01). Additionally, FW in the hippocampus, entorhinal cortex, nucleus basalis of Meynert, and locus coeruleus to transentorhinal cortex tract positively correlated with all five cognitive impairment metrics, and neurofilament light chain levels (mean r2 = 0.10; pfdr<0.05).Conclusions:These results show that higher FW is associated with greater clinical diagnosis severity, cognitive impairment, and neurofilament light chain. They also suggest that FW elevation occurs in the locus coeruleus to transentorhinal cortex tract, nucleus basalis of Meynert, and hippocampus in the transition from CN to EMCI, while other basal forebrain regions and the entorhinal cortex are not affected until a later stage of AD. FW is a clinically relevant and non-invasive early marker of structural changes related to cognitive impairment.

Hippocampal Volume Influences The Correlations Between White Matter Disruption and Tau Protein in aMCI and mild AD

Background: Alzheimer’s disease (AD) is classically considered a grey matter (GM) disease that starts in the transentorhinal cortex and spreads to limbic and neocortical regions. However, white matter (WM) damage could be more severe and widespread than expected cortical atrophy. The role of AD biomarkers and WM integrity throughout the brain is unclear, especially in amnestic Mild Cognitive Impairment (aMCI) patients, a possible prodromal AD dementia stage. If WM damage can be detected even before the development of cortical atrophy and overt dementia and in the AD process, Aβ42 Tau (and its phosphorylated form) could directly affect WM. Methods: We analyzed in this study 183 individuals - 48 aMCI in the AD continuum (altered CSF Aβ42), 30 patients with very mild or mild AD dementia and 105 normal controls. All subjects underwent neuropsychological evaluation and MRI exams. aMCI and mild AD individuals were also submitted to CSF puncture to evaluate AD biomarkers.Results: We observed several significant differences in WM integrity regarding the DTI measures between individuals and we found significant correlations between fornix and right cingulum hippocampal tracts and Tau and p-Tau proteins. Conclusions: We hypothesize that significant correlations with tracts anatomically far from more well-established GM atrophic regions, like medial temporal lobes, would support a more direct effect of pathological proteins on WM, whereas medial temporal lobe (MTL) correlations would favor WD and/or a direct spreading of pathology from the hippocampus.

Hippocampal Volume Influences the Correlations Between White Matter Disruption and Tau Protein in aMCI and mild AD

BackgroundAlzheimer’s disease (AD) is classically considered a grey matter (GM) disease that starts in transentorhinal cortex and spread to limbic and neocortical regions. However, withe matter (WM) damage could be more severe and widespread than expected cortical atrophy. It is not clear the role of AD biomarkers and WM integrity throughout the brain, especially including amnestic Mild Cognitive Impairment (aMCI) patients, a possible prodromal AD dementia stage, if WM damage can be detected even before the development of cortical atrophy and overt dementia and in AD process, Aβ42 Tau (and its phosphorylated form) could directly affect WM.MethodsWe analyzed in this study 183 individuals - 48 aMCI in the AD continuum (altered CSF Aβ42), 30 patients with very mild or mild AD dementia and 105 normal controls. All subjects underwent neuropsychological evaluation and MRI exam. aMCI and mild AD individuals were also submitted to CSF puncture to evaluate AD biomarkers.ResultsWe observed several significant differences in WM integrity regarding the DTI measures between individuals and we found significant correlations between fornix and right cingulum hippocampal tracts and Tau and p-Tau proteins.ConclusionsWe hypothesize that significant correlations with tracts anatomically far from more well-established GM atrophic regions, like medial temporal lobes, would support a more direct effect of pathological proteins on WM, whereas medial temporal lobe (MTL) correlations would favor WD and/or a direct spreading of pathology from hippocampus.

18F-MK-6240 PET for early and late detection of neurofibrillary tangles

Braak stages of tau neurofibrillary tangle accumulation have been incorporated in the criteria for the neuropathological diagnosis of Alzheimer’s disease. It is expected that Braak staging using brain imaging can stratify living individuals according to their individual patterns of tau deposition, which may prove crucial for clinical trials and practice. However, previous studies using the first-generation tau PET agents have shown a low sensitivity to detect tau pathology in areas corresponding to early Braak histopathological stages (∼20% of cognitively unimpaired elderly with tau deposition in regions corresponding to Braak I–II), in contrast to ∼80–90% reported in post-mortem cohorts. Here, we tested whether the novel high affinity tau tangles tracer 18F-MK-6240 can better identify individuals in the early stages of tau accumulation. To this end, we studied 301 individuals (30 cognitively unimpaired young, 138 cognitively unimpaired elderly, 67 with mild cognitive impairment, 54 with Alzheimer’s disease dementia, and 12 with frontotemporal dementia) with amyloid-β 18F-NAV4694, tau 18F-MK-6240, MRI, and clinical assessments. 18F-MK-6240 standardized uptake value ratio images were acquired at 90–110 min after the tracer injection. 18F-MK-6240 discriminated Alzheimer’s disease dementia from mild cognitive impairment and frontotemporal dementia with high accuracy (∼85–100%). 18F-MK-6240 recapitulated topographical patterns consistent with the six hierarchical stages proposed by Braak in 98% of our population. Cognition and amyloid-β status explained most of the Braak stages variance (P &lt; 0.0001, R2 = 0.75). No single region of interest standardized uptake value ratio accurately segregated individuals into the six topographic Braak stages. Sixty-eight per cent of the cognitively unimpaired elderly amyloid-β-positive and 37% of the cognitively unimpaired elderly amyloid-β-negative subjects displayed tau deposition, at least in the transentorhinal cortex (Braak I). Tau deposition solely in the transentorhinal cortex was associated with an elevated prevalence of amyloid-β, neurodegeneration, and cognitive impairment (P &lt; 0.0001). 18F-MK-6240 deposition in regions corresponding to Braak IV–VI was associated with the highest prevalence of neurodegeneration, whereas in Braak V–VI regions with the highest prevalence of cognitive impairment. Our results suggest that the hierarchical six-stage Braak model using 18F-MK-6240 imaging provides an index of early and late tau accumulation as well as disease stage in preclinical and symptomatic individuals. Tau PET Braak staging using high affinity tracers has the potential to be incorporated in the diagnosis of living patients with Alzheimer’s disease in the near future.