scholarly journals Alzheimer's Disease Including Focal Presentations

2019 ◽  
Vol 39 (02) ◽  
pp. 213-226 ◽  
Author(s):  
Nicolas Villain ◽  
Bruno Dubois
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Medial Temporal Lobe ◽  
Chronic Traumatic Encephalopathy ◽  
Hippocampal Sclerosis ◽  
Clinical Status ◽  
Lewy Body Disease ◽  
Epidemiological Data ◽  
Cortical Atrophy ◽  
Age Related

AbstractAlzheimer's disease (AD) is the commonest neurodegenerative disease and the most frequent cause of dementia. It affects 30 million people worldwide. Current research criteria focus on biomarkers' status for amyloid and tau using positron emission tomography and cerebrospinal fluid analysis, independent of clinical status. Current epidemiological data, which mostly rely on biomarker-undetermined AD cases, have highlighted ApoE4 and age as the main risk factors. Rare autosomal dominant mutations also account for a small fraction of early-onset AD. The main clinical phenotype at presentation is the amnestic phenotype targeting episodic memory. This is followed by rarer phenotypes such as posterior cortical atrophy, logopenic variant of primary progressive aphasia, frontal variant AD, corticobasal syndrome, and other even rarer presentations mimicking language variants of frontotemporal dementia. Main differential diagnoses include hippocampal sclerosis with TDP-43, primary age-related tauopathy, argyrophilic grain disease, frontotemporal lobar degeneration, Lewy body disease, chronic traumatic encephalopathy as well as nondegenerative disorders such as cerebrovascular disease, chronic alcohol consumption, limbic encephalitis, medial temporal lobe epilepsy, and others. Co-occurrence of AD pathology with other neurodegenerative and vascular diseases is common and increases with age. This presents a challenge in current clinical practice due to a lack of reliable biomarkers for non-AD neurodegenerative diseases.

scholarly journals Dementia is strongly associated with medial temporal atrophy even after accounting for neuropathologies

2021 ◽  
Author(s):  
Davis Christopher Woodworth ◽  
Nasim Sheikh-Bahaei ◽  
Kiana A Scambray ◽  
Michael J Phelan ◽  
Mari Perez-Rosendahl ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Temporal Lobe ◽  
Medial Temporal Lobe ◽  
Hippocampal Sclerosis ◽  
Clinical Status ◽  
Amyloid Angiopathy ◽  
Linear Regression Models ◽  
Partial Correlations

Objective: Brain atrophy is associated with degenerative neuropathologies as well as clinical status of dementia. Whether dementia influences atrophy independent of neuropathologies is not known. In this study, we examined the pattern of atrophy associated with dementia while accounting for the most common dementia-related neuropathologies. Methods: We used data from National Alzheimer's Coordinating Center (NACC, N=129) and Alzheimer's Disease Neuroimaging Initiative (ADNI, N=47) participants with suitable in-vivo 3D-T1w MRI and autopsy data. We determined dementia status at visit closest to MRI. We examined the following dichotomized neuropathological variables: Alzheimer's disease neuropathology, hippocampal sclerosis, Lewy Bodies, cerebral amyloid angiopathy, atherosclerosis. Voxel-based morphometry (VBM) identified areas associated with dementia after accounting for neuropathologies. Identified regions of interest were further analyzed. We used multiple linear regression models adjusted for neuropathologies and demographic variables. Results: We found strong associations for dementia with volumes of the hippocampus, amygdala, and parahippocampus (semi-partial correlations≥0.28, P<0.0001 for all regions in NACC; semi-partial correlations≥0.35, P≤0.01 for hippocampus and parahippocampus in ADNI). Dementia status accounted for more unique variance in atrophy in these structures (~8%) compared with neuropathological variables; the only exception was hippocampal sclerosis which accounted for more variance in hippocampal atrophy (10%). Conclusion: Even after accounting for the most common neuropathologies, dementia still had among the strongest correlations with atrophy of medial temporal lobe structures. This suggests that atrophy of the medial temporal lobe is most related to clinical status of dementia as opposed to Alzheimer's or other neuropathologies.

scholarly journals Cryo-EM structures of tau filaments from Alzheimer’s disease with PET ligand APN-1607

2021 ◽  
Vol 141 (5) ◽  
pp. 697-708
Author(s):  
Yang Shi ◽  
Alexey G. Murzin ◽  
Benjamin Falcon ◽  
Alexander Epstein ◽  
Jonathan Machin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules ◽  
Binding Sites ◽  
Binding Activity ◽  
Cortical Atrophy ◽  
Binding Modes ◽  
Major Site ◽  
Age Related ◽  
Positron Emission

AbstractTau and Aβ assemblies of Alzheimer’s disease (AD) can be visualized in living subjects using positron emission tomography (PET). Tau assemblies comprise paired helical and straight filaments (PHFs and SFs). APN-1607 (PM-PBB3) is a recently described PET ligand for AD and other tau proteinopathies. Since it is not known where in the tau folds PET ligands bind, we used electron cryo-microscopy (cryo-EM) to determine the binding sites of APN-1607 in the Alzheimer fold. We identified two major sites in the β-helix of PHFs and SFs and a third major site in the C-shaped cavity of SFs. In addition, we report that tau filaments from posterior cortical atrophy (PCA) and primary age-related tauopathy (PART) are identical to those from AD. In support, fluorescence labelling showed binding of APN-1607 to intraneuronal inclusions in AD, PART and PCA. Knowledge of the binding modes of APN-1607 to tau filaments may lead to the development of new ligands with increased specificity and binding activity. We show that cryo-EM can be used to identify the binding sites of small molecules in amyloid filaments.

scholarly journals The Neuropathological Diagnosis of Alzheimer’s Disease—The Challenges of Pathological Mimics and Concomitant Pathology

2020 ◽  
Vol 10 (8) ◽  
pp. 479 ◽  
Author(s):  
Andrew King ◽  
Istvan Bodi ◽  
Claire Troakes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Symptoms ◽  
Chronic Traumatic Encephalopathy ◽  
Lewy Bodies ◽  
Vascular Pathology ◽  
Cytoplasmic Inclusions ◽  
Age Related ◽  
Staining Techniques ◽  
Argyrophilic Grain

The definitive diagnosis of Alzheimer’s disease (AD) rests with post-mortem neuropathology despite the advent of more sensitive scanning and the search for reliable biomarkers. Even though the classic neuropathological features of AD have been known for many years, it was only relatively recently that more sensitive immunohistochemistry for amyloid beta (Aβ) and hyperphosphorylated tau (HP-tau) replaced silver-staining techniques. However, immunohistochemistry against these and other proteins has not only allowed a more scientific evaluation of the pathology of AD but also revealed some mimics of HP-tau pathological patterns of AD, including age-related changes, argyrophilic grain disease and chronic traumatic encephalopathy. It also highlighted a number of cases of AD with significant additional pathology including Lewy bodies, phosphorylated TDP-43 (p-TDP-43) positive neuronal cytoplasmic inclusions and vascular pathology. This concomitant pathology can cause a number of challenges including the evaluation of the significance of each pathological entity in the make-up of the clinical symptoms, and the threshold of each individual pathology to cause dementia. It also raises the possibility of underlying common aetiologies. Furthermore, the concomitant pathologies could provide explanations as to the relative failure of clinical trials of anti-Aβ therapy in AD patients.

scholarly journals Tau immunophenotypes in chronic traumatic encephalopathy recapitulate those of ageing and Alzheimer’s disease

Brain ◽  
2020 ◽  
Vol 143 (5) ◽  
pp. 1572-1587 ◽  
Author(s):  
John D Arena ◽  
Douglas H Smith ◽  
Edward B Lee ◽  
Garrett S Gibbons ◽  
David J Irwin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disease ◽  
Chronic Traumatic Encephalopathy ◽  
Cell Types ◽  
Tau Pathology ◽  
Post Translational Modifications ◽  
Age Related ◽  
History Of ◽  
Severe Tbi

Abstract Traumatic brain injury (TBI) is a risk factor for neurodegenerative disease, including chronic traumatic encephalopathy (CTE). Preliminary consensus criteria define the pathognomonic lesion of CTE as patchy tau pathology within neurons and astrocytes at the depths of cortical sulci. However, the specific tau isoform composition and post-translational modifications in CTE remain largely unexplored. Using immunohistochemistry, we performed tau phenotyping of CTE neuropathologies and compared this to a range of tau pathologies, including Alzheimer’s disease, primary age-related tauopathy, ageing-related tau astrogliopathy and multiple subtypes of frontotemporal lobar degeneration with tau inclusions. Cases satisfying preliminary consensus diagnostic criteria for CTE neuropathological change (CTE-NC) were identified (athletes, n = 10; long-term survivors of moderate or severe TBI, n = 4) from the Glasgow TBI Archive and Penn Neurodegenerative Disease Brain Bank. In addition, material from a range of autopsy-proven ageing-associated and primary tauopathies in which there was no known history of exposure to TBI was selected as non-injured controls (n = 32). Each case was then stained with a panel of tau antibodies specific for phospho-epitopes (PHF1, CP13, AT100, pS262), microtubule-binding repeat domains (3R, 4R), truncation (Tau-C3) or conformation (GT-7, GT-38) and the extent and distribution of staining assessed. Cell types were confirmed with double immunofluorescent labelling. Results demonstrate that astroglial tau pathology in CTE is composed of 4R-immunoreactive thorn-shaped astrocytes, echoing the morphology and immunophenotype of astrocytes encountered in ageing-related tau astrogliopathy. In contrast, neurofibrillary tangles of CTE contain both 3R and 4R tau, with post-translational modifications and conformations consistent with Alzheimer’s disease and primary age-related tauopathy. Our observations establish that the astroglial and neurofibrillary tau pathologies of CTE are phenotypically distinct from each other and recapitulate the tau immunophenotypes encountered in ageing and Alzheimer’s disease. As such, the immunohistochemical distinction of CTE neuropathology from other mixed 3R/4R tauopathies of Alzheimer’s disease and ageing may rest solely on the pattern and distribution of pathology.

scholarly journals Errors in the management of patients with Alzheimer's disease: analysis of problems and ways of their solution

2019 ◽  
Vol 11 (4) ◽  
pp. 141-146
Author(s):  
A. Yu. Emelin ◽  
I. V. Litvinenko ◽  
V. Yu. Lobzin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Pathological Condition ◽  
Epidemiological Data ◽  
Vascular Risk ◽  
Age Related ◽  
Dyscirculatory Encephalopathy ◽  
Cerebral Dysfunction ◽  
Chronic Brain Ischemia ◽  
Disease Analysis

Epidemiological data show that Alzheimer's disease (AD) is the most common cause of acquired cognitive impairment (CI). At the same time, according to statistics, vascular CI and vascular dementia predominate in Russia, which is mainly due to imperfect diagnosis, when any pathological condition associated with cerebral dysfunction in a patient with vascular risk factors is interpreted as dyscirculatory encephalopathy or chronic brain ischemia. However, this can be asthenoneurotic syndrome, migraine, vestibular dysfunction, and a number of neurodegenerative diseases, the most common condition of which is certainly AD. What is more, the treatment of age-related diseases, with the exception of acute vascular disease, is receiving manifestly inadequate attention. All this leads to the lack of a unified methodology for the management of these patients, to the impossibility to have adequate primary medical care, to the low detection rate of CI, to the prescription of drugs without appropriate indications, and to the denial of psychological correction methods. The review highlights the challenges facing the management of patients with AD and the possible ways of their solution.

scholarly journals Medial Temporal Lobe Subregional Atrophy in Aging and Alzheimer's Disease: A Longitudinal Study

2021 ◽  
Vol 13 ◽  
Author(s):  
Léa Chauveau ◽  
Elizabeth Kuhn ◽  
Cassandre Palix ◽  
Francesca Felisatti ◽  
Valentin Ourry ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Temporal Lobe ◽  
Medial Temporal Lobe ◽  
Adult Lifespan ◽  
Parahippocampal Cortex ◽  
Age Related ◽  
Preclinical Ad ◽  
Brodmann Areas ◽  
Over Time

Medial temporal lobe (MTL) atrophy is a key feature of Alzheimer's disease (AD), however, it also occurs in typical aging. To enhance the clinical utility of this biomarker, we need to better understand the differential effects of age and AD by encompassing the full AD-continuum from cognitively unimpaired (CU) to dementia, including all MTL subregions with up-to-date approaches and using longitudinal designs to assess atrophy more sensitively. Age-related trajectories were estimated using the best-fitted polynomials in 209 CU adults (aged 19–85). Changes related to AD were investigated among amyloid-negative (Aβ−) (n = 46) and amyloid-positive (Aβ+) (n = 14) CU, Aβ+ patients with mild cognitive impairment (MCI) (n = 33) and AD (n = 31). Nineteen MCI-to-AD converters were also compared with 34 non-converters. Relationships with cognitive functioning were evaluated in 63 Aβ+ MCI and AD patients. All participants were followed up to 47 months. MTL subregions, namely, the anterior and posterior hippocampus (aHPC/pHPC), entorhinal cortex (ERC), Brodmann areas (BA) 35 and 36 [as perirhinal cortex (PRC) substructures], and parahippocampal cortex (PHC), were segmented from a T1-weighted MRI using a new longitudinal pipeline (LASHiS). Statistical analyses were performed using mixed models. Adult lifespan models highlighted both linear (PRC, BA35, BA36, PHC) and nonlinear (HPC, aHPC, pHPC, ERC) trajectories. Group comparisons showed reduced baseline volumes and steeper volume declines over time for most of the MTL subregions in Aβ+ MCI and AD patients compared to Aβ− CU, but no differences between Aβ− and Aβ+ CU or between Aβ+ MCI and AD patients (except in ERC). Over time, MCI-to-AD converters exhibited a greater volume decline than non-converters in HPC, aHPC, and pHPC. Most of the MTL subregions were related to episodic memory performances but not to executive functioning or speed processing. Overall, these results emphasize the benefits of studying MTL subregions to distinguish age-related changes from AD. Interestingly, MTL subregions are unequally vulnerable to aging, and those displaying non-linear age-trajectories, while not damaged in preclinical AD (Aβ+ CU), were particularly affected from the prodromal stage (Aβ+ MCI). This volume decline in hippocampal substructures might also provide information regarding the conversion from MCI to AD-dementia. All together, these findings provide new insights into MTL alterations, which are crucial for AD-biomarkers definition.

scholarly journals High-Dimensional Medial Lobe Morphometry: An Automated MRI Biomarker for the New AD Diagnostic Criteria

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Simon Duchesne ◽  
Fernando Valdivia ◽  
Abderazzak Mouiha ◽  
Nicolas Robitaille
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Temporal Lobe ◽  
Medial Temporal Lobe ◽  
Clinical Status ◽  
High Dimensional ◽  
Medial Temporal Lobe Atrophy ◽  
Magnetic Resonance Imaging Mri ◽  
Lobe Atrophy

Introduction. Medial temporal lobe atrophy assessment via magnetic resonance imaging (MRI) has been proposed in recent criteria as anin vivodiagnostic biomarker of Alzheimer’s disease (AD). However, practical application of these criteria in a clinical setting will require automated MRI analysis techniques. To this end, we wished to validate our automated, high-dimensional morphometry technique to the hypothetical prediction of future clinical status from baseline data in a cohort of subjects in a large, multicentric setting, compared to currently known clinical status for these subjects.Materials and Methods. The study group consisted of 214 controls, 371 mild cognitive impairment (147 having progressed to probable AD and 224 stable), and 181 probable AD from the Alzheimer’s Disease Neuroimaging Initiative, with data acquired on 58 different 1.5 T scanners. We measured the sensitivity and specificity of our technique in a hierarchical fashion, first testing the effect of intensity standardization, then between different volumes of interest, and finally its generalizability for a large, multicentric cohort.Results. We obtained 73.2% prediction accuracy with 79.5% sensitivity for the prediction of MCI progression to clinically probable AD. The positive predictive value was 81.6% for MCI progressing on average within 1.5 (0.3 s.d.) year.Conclusion. With high accuracy, the technique’s ability to identify discriminant medial temporal lobe atrophy has been demonstrated in a large, multicentric environment. It is suitable as an aid for clinical diagnostic of AD.

scholarly journals TDP-43 Pathology in Alzheimer’s Disease

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Axel Meneses ◽  
Shunsuke Koga ◽  
Justin O’Leary ◽  
Dennis W. Dickson ◽  
Guojun Bu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rna Splicing ◽  
Inclusion Bodies ◽  
Hippocampal Sclerosis ◽  
Regulation Of Gene Expression ◽  
Cytoplasmic Inclusion ◽  
Age Related ◽  
Cytoplasmic Inclusion Bodies ◽  
Lateral Sclerosis

AbstractTransactive response DNA binding protein of 43 kDa (TDP-43) is an intranuclear protein encoded by the TARDBP gene that is involved in RNA splicing, trafficking, stabilization, and thus, the regulation of gene expression. Cytoplasmic inclusion bodies containing phosphorylated and truncated forms of TDP-43 are hallmarks of amyotrophic lateral sclerosis (ALS) and a subset of frontotemporal lobar degeneration (FTLD). Additionally, TDP-43 inclusions have been found in up to 57% of Alzheimer’s disease (AD) cases, most often in a limbic distribution, with or without hippocampal sclerosis. In some cases, TDP-43 deposits are also found in neurons with neurofibrillary tangles. AD patients with TDP-43 pathology have increased severity of cognitive impairment compared to those without TDP-43 pathology. Furthermore, the most common genetic risk factor for AD, apolipoprotein E4 (APOE4), is associated with increased frequency of TDP-43 pathology. These findings provide strong evidence that TDP-43 pathology is an integral part of multiple neurodegenerative conditions, including AD. Here, we review the biology and pathobiology of TDP-43 with a focus on its role in AD. We emphasize the need for studies on the mechanisms that lead to TDP-43 pathology, especially in the setting of age-related disorders such as AD.

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