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 Structure-based Classification of Tauopathies

2021 ◽  
Author(s):  
Yang Shi ◽  
Wenjuan Zhang ◽  
Yang Yang ◽  
Alexey G Murzin ◽  
Benjamin Falcon ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Chronic Traumatic Encephalopathy ◽  
Corticobasal Degeneration ◽  
Familial Danish Dementia ◽  
Age Related ◽  
Argyrophilic Grain ◽  
Globular Glial Tauopathy ◽  
Ordered Assembly

Ordered assembly of the tau protein into filaments characterizes multiple neurodegenerative diseases, which are called tauopathies. We previously reported that by electron cryo-microscopy (cryo-EM), tau filament structures from Alzheimer's disease, chronic traumatic encephalopathy (CTE), Pick's disease and corticobasal degeneration (CBD) are distinct. Here we show that the structures of tau filaments from typical and atypical progressive supranuclear palsy (PSP), the most common tauopathy after Alzheimer's disease, define a previously unknown, three-layered fold. Moreover, the tau filament structures from globular glial tauopathy (GGT, Types I and II) are similar to those from PSP. The tau filament fold of argyrophilic grain disease (AGD) differs from the above and resembles the four-layered CBD fold. The majority of tau filaments from aging-related tau astrogliopathy (ARTAG) also have the AGD fold. Surprisingly, tau protofilament structures from inherited cases with mutations +3/+16 in intron 10 of MAPT, the microtubule-associated protein tau gene, are identical to those from AGD, suggesting that a relative overproduction of four-repeat tau can give rise to the AGD fold. Finally, tau filament structures from cases of familial British dementia (FBD) and familial Danish dementia (FDD) are the same as those from Alzheimer's disease and primary age-related tauopathy (PART). These structures provide the basis for a classification of tauopathies that also allows identification of new entities, as we show here for a case diagnosed as PSP, but with abundant spherical 4R tau inclusions in limbic and other brain areas. The structures of the tau fold of this new disease (Limbic-predominant Neuronal inclusion body 4R Tauopathy, LNT) were intermediate between those of GGT and PSP.

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 Age-Related Vascular Pathology in Transgenic Mice Expressing Presenilin 1-Associated Familial Alzheimer's Disease Mutations

2010 ◽  
Vol 176 (1) ◽  
pp. 353-368 ◽  
Author(s):  
Miguel A. Gama Sosa ◽  
Rita De Gasperi ◽  
Anne B. Rocher ◽  
Athena Ching-Jung Wang ◽  
William G.M. Janssen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Vascular Pathology ◽  
Presenilin 1 ◽  
Familial Alzheimer’S Disease ◽  
Age Related ◽  
Disease Mutations ◽  
Familial Alzheimer's Disease

scholarly journals Revised NIA-AA criteria for the diagnosis of Alzheimer's disease: a step forward but not yet ready for widespread clinical use

2011 ◽  
Vol 23 (8) ◽  
pp. 1191-1196 ◽  
Author(s):  
Giovanni B. Frisoni ◽  
Bengt Winblad ◽  
John T. O'Brien
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Diagnostic Criteria ◽  
Time Course ◽  
Clinical Medicine ◽  
Clinical Symptoms ◽  
Lewy Bodies ◽  
Pathological Study ◽  
Subcortical Vascular Dementia ◽  
Communicative Disorders

In clinical medicine, diagnostic criteria are not only useful everyday tools for the practicing physician, but also represent a conceptual concentrate of the understanding of the etiology and pathophysiology of diseases at a given point in time. Although different sets of diagnostic criteria for Alzheimer's disease (AD) have been developed, the most widely used and best validated by clinico-pathological study to date are the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke – Alzheimer's Disease and Related Disorders Association) criteria which were published in 1984 (McKhann et al., 1984). These criteria are largely based on the exclusion of other conditions that may cause dementia and can be succinctly but fairly summarized as defining AD as an “acquired progressive cognitive, behavioral, and functional impairment with no other obvious cause”. Clearly, the NINCDS-ADRDA criteria were etiology- and pathophysiology-agnostic in that they failed to point at any specific etiology, not even a degenerative one. They were also developed before other important causes of dementia, such as dementia with Lewy bodies, fronto-temporal dementia and subcortical vascular dementia had been fully described and characterized. The recent publication of a substantially revised version of these criteria (Sperling et al. 2011; Albert et al., 2011; McKhann et al., 2011), heralded by a largely European initiative four years ago (Dubois et al., 2007) has been greeted with great interest by the field. The newly proposed criteria reflect the substantial insights on disease pathophysiology gained over the last decades, especially regarding the molecular pathology of AD and the time course of such pathology in relation to clinical symptoms and disease.

scholarly journals Fiber Tracts Anomalies in APPxPS1 Transgenic Mice Modeling Alzheimer's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
H. Chen ◽  
S. Epelbaum ◽  
B. Delatour
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Clinical Symptoms ◽  
Anterior Commissure ◽  
Fiber Tract ◽  
Fiber Tracts ◽  
Age Related ◽  
The Impact ◽  
The Brain

Amyloid beta (A) peptides are known to accumulate in the brain of patients with Alzheimer's disease (AD). However, the link between brain amyloidosis and clinical symptoms has not been elucidated and could be mediated by secondary neuropathological alterations such as fiber tracts anomalies. In the present study, we have investigated the impact of A overproduction in APPxPS1 transgenic mice on the integrity of forebrain axonal bundles (corpus callosum and anterior commissure). We found evidence of fiber tract volume reductions in APPxPS1 mice that were associated with an accelerated age-related loss of axonal neurofilaments and a myelin breakdown. The severity of these defects was neither correlated with the density of amyloid plaques nor associated with cell neurodegeneration. Our data suggest that commissural fiber tract alterations are present in A-overproducing transgenic mice and that intracellular A accumulation preceding extracellular deposits may act as a trigger of such morphological anomalies.

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