Stepwise regression models with 18 F-MK6240 PET explaining variability in composite cognitive measures in right hemisphere models.

Stepwise regression models with 18 F-MK6240 PET explaining variability in composite cognitive measures in right hemisphere models.

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Introduction The accumulation of neurofibrillary tau tangles, a neuropathological hallmark of Alzheimer’s disease (AD), occurs in medial temporal lobe (MTL) regions early in the disease process, with some of the earliest deposits localized to subregions of the entorhinal cortex. Although functional specialization of entorhinal cortex subregions has...

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... from the stepwise linear regression analyses are presented in Table 2, and detailed results for each model are described below. Figure 3B] as significant predictors in the final model. ...
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... test whether our findings were primarily driven by a subgroup of participants, we performed follow-up sensitivity analyses where stepwise regression analyses were computed separately for each diagnostic group. Supplementary Table S2. ...

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... 8 These tangles are closely linked to the loss of cognitive function, leading to deficits in specific domains such as memory and language. [9][10][11] The relationship between the spatial patterns of tau tangles in the brain and domain-specific decline in cognitive abilities highlights the importance of understanding tau pathophysiology, particularly in the preclinical stages of the disease. ...
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INTRODUCTION The spatial heterogeneity of tau deposition is closely linked to clinical variants of Alzheimer's disease (AD). Detecting these patterns in the preclinical stage is challenging, but second‐generation tau tracers provide a unique opportunity to do so. METHODS We used independent component analysis (ICA) and tau positron emission tomography (PET) imaging with the 18F‐MK6240 tracer in 590 cognitively healthy adults (mean age 66.58 ± 5.13 years, 340 females) to identify tau patterns in the preclinical stage. RESULTS Using all individuals, seven distinct patterns emerged, with medial temporal lobe (MTL) involvement associated with age, Aβ burden, apolipoprotein E (APOE) genotype, and plasma total tau. Bilateral amygdala‐hippocampus tau deposition was associated negatively with memory (t = −2.64, p < 0.01), while broader neocortical patterns, especially asymmetric ones, were linked to deficits in language (t < −3.13, p < 0.002) and reasoning (t < −2.63, p < 0.01). DISCUSSION These findings advance our understanding of preclinical tau heterogeneity, offering new insights for early AD intervention. Highlights Seven tau deposition patterns were identified in preclinical stages of AD, including medial temporal lobe and asymmetric neocortical patterns. Medial temporal lobe patterns were strongly linked to age, APOE genotype, Aβ burden, and plasma total tau levels. Neocortical patterns, especially asymmetric ones, were linked to domain‐specific cognitive deficits, notably in language and reasoning. This research highlights the potential of using tau deposition patterns for early detection and tailoring interventions in preclinical AD.
... 12 Recent studies have used advances in image resolution to show that subregions of the ERC, particularly the lateral ERC including the transentorhinal cortex, provide greater neuroanatomical specificity and increased sensitivity in assessing progression in patients with amnestic MCI. [13][14][15][16][17] Therefore, the current study used an analysis of the ERC and adjacent subregions to assess structural changes over 78 weeks in APOE ε4 non-carrier participants with MCI due to AD who completed participation in the HOPE4MCI study. Blood samples collected at the week 78 visit were analyzed for blood plasma biomarkers of AD including the amyloid beta (Aβ)42/40 ratio reflecting amyloid deposition, phosphorylated tau (p-tau) 181 as a measure of tau accumulation, and neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) as general measures of neurodegeneration. ...
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Introduction Hippocampal hyperactivity is a hallmark of prodromal Alzheimer's disease (AD) that predicts progression in patients with amnestic mild cognitive impairment (aMCI). AGB101 is an extended‐release formulation of levetiracetam in the dose range previously demonstrated to normalize hippocampal activity and improve cognitive performance in aMCI. The HOPE4MCI study was a 78‐week trial to assess the progression of MCI due to AD. As reported in Mohs et al., the decline in the Clinical Dementia Rating Sum of Boxes score (CDR‐SB) was reduced by 40% in apolipoprotein E (APOE) ε4 non‐carriers over the 78‐week duration of the study with a negligible effect in carriers. Here we report an exploratory analysis of the effects of AGB101 on neuroimaging and biomarker measures in the 44 APOE ε4 non‐carriers who completed the 78‐week protocol. Methods Structural magnetic resonance imaging scans obtained at baseline and after 78 weeks were analyzed using the Automated Segmentation of Hippocampal Subfields software providing volume measures of key structures of the medial temporal lobe relevant to AD progression. Blood samples collected at 78 weeks in the study were analyzed for plasma biomarkers. Results Treatment with AGB101 significantly reduced atrophy of the left entorhinal cortex (ERC) compared to placebo. This reduction in atrophy was correlated with less decline in the CDR‐SB score over 78 weeks and with lower neurofilament light chain (NfL), a marker of neurodegeneration. Discussion The HOPE4MCI study showed that APOE ε4 non‐carriers treated with AGB101 demonstrated a substantially more favorable treatment effect compared to carriers. Here we report that treatment with AGB101 in non‐carriers of APOE ε4 significantly reduced atrophy of the left ERC over 78 weeks. That reduction in atrophy was closely coupled with the change in CDR‐SB and with plasma NfL indicative of neurodegeneration in the brain. These exploratory analyses are consistent with a reduction in neurodegeneration in APOE ε4 non‐carriers treated with AGB101 before a clinical diagnosis of dementia. Highlights AGB101 slows entorhinal cortex (ERC) atrophy in apolipoprotein E (APOE) ε4 non‐carriers with mild cognitive impairment (MCI) due to Alzheimer's disease (AD). Slowing ERC atrophy by AGB101 is associated with less Clinical Dementia Rating Sum of Boxes decline. Slowing ERC atrophy by AGB101 is associated with lower neurofilament light chain. AGB101 treatment reduces neurodegeneration in APOE ε4 non‐carriers with MCI due to AD.
... Advancements in MRI and image processing techniques have enabled in vivo imaging and quantitative analysis of the anatomically and functionally distinct subfields/subregions that make up the hippocampus and MTL [36,74,101,104]. Volume and thickness measurements of these subregions have been used in aging and neurodegenerative disease studies examining longitudinal subregional atrophy patterns, functional connectivity, and positron emission tomography (PET) imaging of amyloid and tau pathology [3,13,34,76,100]. ...
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The medial temporal lobe (MTL) is a hotspot for neuropathology, and measurements of MTL atrophy are often used as a biomarker for cognitive decline associated with neurodegenerative disease. Due to the aggregation of multiple proteinopathies in this region, the specific relationship of MTL atrophy to distinct neuropathologies is not well understood. Here, we develop two quantitative algorithms using deep learning to measure phosphorylated tau (p-tau) and TDP-43 (pTDP-43) pathology, which are both known to accumulate in the MTL and are associated with MTL neurodegeneration. We focus on these pathologies in the context of Alzheimer’s disease (AD) and limbic predominant age-related TDP-43 encephalopathy (LATE) and apply our deep learning algorithms to distinct histology sections, on which MTL subregions were digitally annotated. We demonstrate that both quantitative pathology measures show high agreement with expert visual ratings of pathology and discriminate well between pathology stages. In 140 cases with antemortem MR imaging, we compare the association of semi-quantitative and quantitative postmortem measures of these pathologies in the hippocampus with in vivo structural measures of the MTL and its subregions. We find widespread associations of p-tau pathology with MTL subregional structural measures, whereas pTDP-43 pathology had more limited associations with the hippocampus and entorhinal cortex. Quantitative measurements of p-tau pathology resulted in a significantly better model of antemortem structural measures than semi-quantitative ratings and showed strong associations with cortical thickness and volume. By providing a more granular measure of pathology, the quantitative p-tau measures also showed a significant negative association with structure in a severe AD subgroup where semi-quantitative ratings displayed a ceiling effect. Our findings demonstrate the advantages of using quantitative neuropathology to understand the relationship of pathology to structure, particularly for p-tau, and motivate the use of quantitative pathology measurements in future studies. Supplementary Information The online version contains supplementary material available at 10.1007/s00401-024-02789-9.
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Background Low-intensity focused ultrasound (LIFU), a non-invasive targeted brain stimulation technology, has shown promise for therapeutic applications in Alzheimer's disease (AD) patients. Despite its potential, the implications of repeated LIFU neuromodulation in AD patients remain to be investigated. Objective This pilot study evaluated the safety and potential to improve cognition and functional connectivity following repeated LIFU treatment in AD patients. Methods Ten early-stage AD patients underwent six sessions of neuronavigation-guided LIFU targeting the left dorsolateral prefrontal cortex (DLPFC) within 2–3 weeks, alongside ongoing standard pharmacotherapy. Neuropsychological assessments and resting-state functional magnetic resonance imaging were performed at baseline and eight weeks post-treatment. Results Memory performance (p = 0.02) and functional connectivity between the left DLPFC and both the left perirhinal cortex and left dorsomedial prefrontal cortex (corrected p < 0.05) significantly improved from baseline. Additionally, enhancements in memory performance were positively correlated with increases in functional connectivity of the left DLPFC with the left perirhinal cortex (Kendall's tau = 0.56, p = 0.03). No adverse events were reported during the LIFU treatments or at the subsequent follow-up. Conclusions LIFU may have the therapeutic potential to enhance both brain network connectivity and memory functions in AD patients. Our results provide a basis for further research, including randomized sham-controlled trials and optimization of stimulation protocols, on LIFU as a supplementary or alternative treatment option for AD. Trial registration Clinical Research Information Service, KCT0008169, Registered on 10 February 2023
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Positron Emission Tomography (PET) early Braak staging might be susceptible to anatomical variability and reduced dimensions of medial temporal lobe (MTL) structures. Optimized atlases should improve staging accuracy by accounting to size and anatomical variability. This study aimed to compare the accuracy of early tau detection using an optimized MTL segmentation. Six native space MTL structures were used as regions of interest (ROI) for [ 18 F]MK6240 tau-PET images and compared with standard space Braak stage ROIs for 333 participants aged over 55. We used the Rey Auditory Verbal Learning Test (RAVLT) to assess memory. Native and standard space tau-PET stage ROIs were compared, then combined into an optimized MTL atlas. The optimized MTL atlas, informed by native space segmentations, identified more participants with an initial tau accumulation and found an earlier clinically relevant Braak stage III tau accumulation. Standard space approaches can be improved by studying smaller native space ROIs.
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INTRODUCTION The generalizability of neuroimaging and cognitive biomarkers in their sensitivity to detect preclinical Alzheimer's disease (AD) and power to predict progression in large, multisite cohorts remains unclear. METHOD Longitudinal demographics, T1‐weighted magnetic resonance imaging (MRI), and cognitive scores of 3036 cognitively unimpaired (CU) older adults (amyloid beta [Aβ]‐negative/positive [A–/A+]: 1270/1558) were included. Cross‐sectional and longitudinal cognition and medial temporal lobe (MTL) structural measures were extracted. Cross‐sectional MTL tau burden (T) was computed from tau positron emission tomography (N = 1095). RESULTS We found cross‐sectional tau and longitudinal structural biomarkers best separated A+ CU from A– CU. A–T+ CU had significantly faster neurodegeneration rate compared to A–T– CU. MTL tau was significantly correlated with MRI and cognitive biomarkers regardless of Aβ status. MTL tau, MRI, and cognition provided complementary information about disease progression. DISCUSSION This large multisite study replicates prior findings in CU older adults, supporting the utility of neuroimaging and cognitive biomarkers in preclinical AD clinical trials and normal aging studies. Highlights We investigated neuroimaging and cognitive biomarkers in 3036 cognitively unimpaired (CU) participants. Medial temporal lobe (MTL) tau and longitudinal MTL atrophy best separate amyloid beta positive (A+) CU from amyloid beta negative (A–) CU. A– tau positive (T+) CU had a significantly faster neurodegeneration rate compared to A–T– CU. MTL tau correlated with structural magnetic resonance imaging (MRI) and cognition regardless of amyloid beta status. Combined baseline MTL tau, MRI, and cognition best predict Alzheimer's disease progression.