Abstract Thanks to its safety and accessibility, magnetic resonance imaging (MRI) is extensively used in clinical routine and research field, largely contributing to our understanding of the ...pathophysiology of neurodegenerative disorders such as Alzheimer’s disease (AD). This review aims to provide a comprehensive overview of the main findings in AD and normal aging over the past twenty years, focusing on the patterns of gray and white matter changes assessed in vivo using MRI. Major progresses in the field concern the segmentation of the hippocampus with novel manual and automatic segmentation approaches, which might soon enable to assess also hippocampal subfields. Advancements in quantification of hippocampal volumetry might pave the way to its broader use as outcome marker in AD clinical trials. Patterns of cortical atrophy have been shown to accurately track disease progression and seem promising in distinguishing among AD subtypes. Disease progression has also been associated with changes in white matter tracts. Recent studies have investigated two areas often overlooked in AD, such as the striatum and basal forebrain, reporting significant atrophy, although the impact of these changes on cognition is still unclear. Future integration of different MRI modalities may further advance the field by providing more powerful biomarkers of disease onset and progression.
Hampel et al. review the role of the cholinergic system in cognition and how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology. They document the ...benefits of cholinergic therapies at various stages of disease, and argue that the weight of the evidence confirms their continued value.
Abstract
Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-β proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer's disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.
During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, ...it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this “silent” stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations.
In this multicenter study on subjective cognitive decline (SCD) in community-based and memory clinic settings, we assessed the (1) incidence of Alzheimer's disease (AD) and non-AD dementia and (2) ...determinants of progression to dementia.
Eleven cohorts provided 2978 participants with SCD and 1391 controls. We estimated dementia incidence and identified risk factors using Cox proportional hazards models.
In SCD, incidence of dementia was 17.7 (95% Poisson confidence interval 15.2-20.3)/1000 person-years (AD: 11.5 9.6-13.7, non-AD: 6.1 4.7-7.7), compared with 14.2 (11.3-17.6) in controls (AD: 10.1 7.7-13.0, non-AD: 4.1 2.6-6.0). The risk of dementia was strongly increased in SCD in a memory clinic setting but less so in a community-based setting. In addition, higher age (hazard ratio 1.1 95% confidence interval 1.1-1.1), lower Mini–Mental State Examination (0.7 0.66-0.8), and apolipoprotein E ε4 (1.8 1.3-2.5) increased the risk of dementia.
SCD can precede both AD and non-AD dementia. Despite their younger age, individuals with SCD in a memory clinic setting have a higher risk of dementia than those in community-based cohorts.
•A large collaborative study indicates subjective cognitive decline (SCD) is a prodrome of Alzheimer's disease and non-Alzheimer's disease dementia.•Incidence of dementia for SCD is 17.7 (95% confidence interval 15.2-20.3)/1000 person-years.•Risk factors for progression from SCD to dementia are age, lower MMSE, and APOE.•SCD in a memory clinic setting increased the risk of dementia.
Summary Alzheimer's disease is a progressive neurodegenerative disease that typically manifests clinically as an isolated amnestic deficit that progresses to a characteristic dementia syndrome. ...Advances in neuroimaging research have enabled mapping of diverse molecular, functional, and structural aspects of Alzheimer's disease pathology in ever increasing temporal and regional detail. Accumulating evidence suggests that distinct types of imaging abnormalities related to Alzheimer's disease follow a consistent trajectory during pathogenesis of the disease, and that the first changes can be detected years before the disease manifests clinically. These findings have fuelled clinical interest in the use of specific imaging markers for Alzheimer's disease to predict future development of dementia in patients who are at risk. The potential clinical usefulness of single or multimodal imaging markers is being investigated in selected patient samples from clinical expert centres, but additional research is needed before these promising imaging markers can be successfully translated from research into clinical practice in routine care.
Introduction
This increasing body of literature indicates that menopause hormonal replacement therapy (MHT) may substantially mitigate the risk of developing late‐life cognitive decline due to ...progressive Alzheimer's disease (AD) pathophysiology. For the first time, we investigated the question whether MHT impacts AD biomarker‐informed pathophysiological dynamics in de‐novo diagnosed menopausal women.
Methods
We analyzed baseline and longitudinal differences between MHT‐taking and ‐not women in terms of concentrations of core pathophysiological AD plasma biomarkers, validated in symptomatic and cognitively healthy individuals, including biomarkers of (1) the amyloid‐β (Aβ) pathway, (2) tau pathophysiology, (3) neuronal loss, and (4) axonal damage and neurodegeneration.
Results
We report a prominent and significant treatment response at the Aβ pathway biomarker level. Women at genetic risk for AD (APOE e4 allele carriers) have particularly shown favorable results from treatment.
Discussion
To our knowledge, we present first prospective clinical evidence on effects of MHT on AD pathophysiology during menopause.
The diagnostic and classificatory performances of all combinations of three core (amyloid β peptide i.e., Aβ1–42, total tau t-tau, and phosphorylated tau) and three novel (neurofilament light chain ...protein, neurogranin, and YKL-40) cerebrospinal fluid biomarkers of neurodegeneration were compared among individuals with mild cognitive impairment (n = 41), Alzheimer's disease dementia (ADD; n = 35), frontotemporal dementia (FTD; n = 9), and cognitively healthy controls (HC; n = 21), using 10-fold cross-validation.
The combinations ranking in the top 10 according to diagnostic accuracy in differentiating between distinct diagnostic categories were identified.
The single biomarkers or biomarker combinations generating the best area under the receiver operating characteristics (AUROCs) were the following: the combination amyloid β peptide + phosphorylated tau + neurofilament light chain for distinguishing between ADD patients and HC (AUROC = 0.86), t-tau for distinguishing between ADD and FTD patients (AUROC = 0.82), and t-tau for distinguishing between FTD patients and HC (AUROC = 0.78).
Novel and established cerebrospinal fluid markers perform with at least fair accuracy in the discrimination between ADD and FTD. The classification of mild cognitive impairment individuals was poor.
•Interest in novel biomarkers of neurodegeneration is growing.•We measured novel and established cerebrospinal fluid biomarkers.•The diagnostic performances of all combinations were investigated.•We identified the biomarker combinations with the highest accuracy.•Longitudinal investigations are required to validate our data.
Acetylcholinesterase inhibitors are approved drugs currently used for the treatment of Alzheimer's disease (AD) dementia. Basal forebrain cholinergic system (BFCS) atrophy is reported to precede both ...entorhinal cortex atrophy and memory impairment in AD, challenging the traditional model of the temporal sequence of topographical pathology associated with AD. We studied the effect of one-year Donepezil treatment on the rate of BFCS atrophy in prodromal AD patients using a double-blind, randomized, placebo-controlled trial of Donepezil (10 mg/day). Reduced annual BFCS rates of atrophy were found in the Donepezil group compared to the Placebo treated arm. Secondary analyses on BFCS subregions demonstrated the largest treatment effects in the Nucleus Basalis of Meynert (NbM) and the medial septum/diagonal band (Ch1/2). Donepezil administered at a prodromal stage of AD seems to substantially reduce the rate of atrophy of the BFCS nuclei with highest concentration of cholinergic neurons projecting to the cortex (NbM), hippocampus and entorhinal cortex (Ch1/2).
Objectives
QyScore® is an imaging analysis tool certified in Europe (CE marked) and the US (FDA cleared) for the automatic volumetry of grey and white matter (GM and WM respectively), hippocampus ...(HP), amygdala (AM), and white matter hyperintensity (WMH). Here we compare QyScore® performances with the consensus of expert neuroradiologists.
Methods
Dice similarity coefficient (DSC) and the relative volume difference (RVD) for GM, WM volumes were calculated on 50 3DT1 images. DSC and the F1 metrics were calculated for WMH on 130 3DT1 and FLAIR images. For each index, we identified thresholds of reliability based on current literature review results. We hypothesized that DSC/F1 scores obtained using QyScore® markers would be higher than the threshold. In contrast, RVD scores would be lower. Regression analysis and Bland–Altman plots were obtained to evaluate QyScore® performance in comparison to the consensus of three expert neuroradiologists.
Results
The lower bound of the DSC/F1 confidence intervals was higher than the threshold for the GM, WM, HP, AM, and WMH, and the higher bounds of the RVD confidence interval were below the threshold for the WM, GM, HP, and AM. QyScore®, compared with the consensus of three expert neuroradiologists, provides reliable performance for the automatic segmentation of the GM and WM volumes, and HP and AM volumes, as well as WMH volumes.
Conclusions
QyScore® represents a reliable medical device in comparison with the consensus of expert neuroradiologists. Therefore, QyScore® could be implemented in clinical trials and clinical routine to support the diagnosis and longitudinal monitoring of neurological diseases.
Key Points
• QyScore® provides reliable automatic segmentation of brain structures in comparison with the consensus of three expert neuroradiologists.
• QyScore® automatic segmentation could be performed on MRI images using different vendors and protocols of acquisition. In addition, the fast segmentation process saves time over manual and semi-automatic methods.
• QyScore® could be implemented in clinical trials and clinical routine to support the diagnosis and longitudinal monitoring of neurological diseases.
Abstract Late-onset and early-onset Alzheimer's disease (LOAD, EOAD) affect different neural systems and may be separate nosographic entities. The most striking differences are in the medial temporal ...lobe, severely affected in LOAD and relatively spared in EOAD. We assessed amygdalar morphology and volume in 18 LOAD and 18 EOAD patients and 36 aged-matched controls and explored their relationship with the hippocampal volume. Three-dimensional amygdalar shape was reconstructed with the radial atrophy mapping technique, hippocampal volume was measured using a manual method. Atrophy was greater in LOAD than EOAD: 25% versus 17% in the amygdala and 20% versus 13% in the hippocampus. In the amygdala, LOAD showed significantly greater tissue loss than EOAD in the right dorsal central, lateral, and basolateral nuclei (20%–30% loss, p < 0.03), all known to be connected to limbic regions. In LOAD but not EOAD, greater hippocampal atrophy was associated with amygdalar atrophy in the left dorsal central and medial nuclei (r = 0.6, p < 0.05) also part of the limbic system. These findings support the notion that limbic involvement is a prominent feature of LOAD but not EOAD.
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