Biomarkers for Differential Diagnosis Between Chronic Traumatic Encephalopathy and Alzheimer Disease: A Systematic Review

ObjectiveTo assess the diagnostic utility of biomarkers that could differentiate Chronic Traumatic Encephalopathy (CTE) from Alzheimer disease (AD).BackgroundCTE is a neurodegenerative disease associated with multiple head trauma. The diagnosis depends on neuropathologic findings postmortem, and patients can present cognitive and behavioral changes. These symptoms can usually be mistaken for other dementias, such as AD, leading to an underestimated frequency of CTE. Therefore, specific biomarkers can be useful for comprehending disease development, diagnosis and prognosis.Design/MethodsWe systematically searched the MEDLINE, Embase and Cochrane databases. We also searched the trial registries and reference lists of articles. We included studies that were relevant to the PICO question posed and analysed different biomarkers. We screened titles and abstracts and if they were pertinent, we assessed the full text and reported results narratively.ResultsTwenty-two studies were identified through database searching. One study was excluded due to duplicity among the databases. Twenty-one articles were assessed for eligibility and 6 were included in the qualitative synthesis. P-Tau and T-tau proteins were indicated as biomarkers of neurodegenerative diseases such as CTE and AD, but not from other tauopathies. Exosomal tau levels are higher in CTE patients than in AD patients, and it might be useful since it is very stable, crosses the blood–brain barrier and reflects their cellular origin. Pathophysiologic differences between CTE and AD are pointed out as a way to find specific biomarkers for CTE. The biomarkers associated with neuroaxonal damage (NFL), glial response with astroglial scarring (GFAP and sTREM2), and microvascular damage with disruption of the blood–brain barrier (cerebrospinal fluid/serum albumin ratio) are promising in that way.ConclusionsBiomarkers that arise from pathophysiologic processes distinct from the 2 diseases, appear to be promising. However, further well-designed studies are needed to assess the real utility of the biomarkers in differential diagnosis between CTE and AD.

Assembly of recombinant tau into filaments identical to those of Alzheimer's disease and chronic traumatic encephalopathy

Abundant filamentous inclusions of tau are characteristic of more than 20 neurodegenerative diseases that are collectively termed tauopathies. Electron cryo-microscopy (cryo-EM) structures of tau amyloid filaments from human brain revealed that different tau folds characterise many different diseases. A lack of laboratory-based model systems to generate these structures has hampered efforts to uncover the molecular mechanisms that underlie tauopathies. Here, we report in vitro assembly conditions with recombinant tau that replicate the structures of filaments from both Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE), as determined by cryo-EM. Our results suggest that post-translational modifications of tau modulate filament assembly, and that previously observed additional densities in AD and CTE filaments may arise from the presence of inorganic salts, like phosphates and sodium chloride. In vitro assembly of tau into disease-relevant filaments will facilitate studies to determine their roles in different diseases, as well as the development of compounds that specifically bind to these structures or prevent their formation.

Unraveling the Influence of K280 Acetylation on the Conformational Features of Tau Core Fragment: A Molecular Dynamics Simulation Study

Abnormal aggregation of the microtubule-associated protein Tau is closely associated with tauopathies, including Alzheimer’s disease and chronic traumatic encephalopathy. The hexapeptide 275VQIINK280 (PHF6*), a fibril-nucleating core motif of Tau, has been shown to play a vital role in the aggregation of Tau. Mounting experiment evidence demonstrated the acetylation of a single-lysine residue K280 in the PHF6* was a critical event for the formation of pathological Tau amyloid deposits. However, the underlying mechanisms by which K280 acetylation affects Tau aggregation at the atomic level remain elusive. In this work, we performed replica exchange molecular dynamics simulations to investigate the influence of acetylation of K280 on the aggregation of PHF6*. Our simulations show that acetylation of K280 not only enhances the self-assembly capability of PHF6* peptides but also increases the β-sheet structure propensity of the PHF6*. The inter-molecular interactions among PHF6* peptides are strengthened by the acetylation of K280, resulting in an increased ordered β-sheet-rich conformations of the PHF6* assemblies along with a decrease of the structural diversity. The residue-pairwise contact frequency analysis shows that K280 acetylation increases the interactions among the hydrophobic chemical groups from PHF6* peptides, which promotes the aggregation of PHF6*. This study offers mechanistic insights into the effects of acetylation on the aggregation of PHF6*, which will be helpful for an in-depth understanding of the relationship between acetylation and Tau aggregation at the molecular level.