The understanding of neurodegenerative diseases, traditionally considered to be well-defined entities with distinguishable clinical phenotypes, has undergone a major shift over the last 20 years. The diagnosis of neurodegenerative diseases primarily requires functional brain imaging techniques or invasive tests such as lumbar puncture to assess cerebrospinal fluid. A new biological approach and research efforts, especially in vivo, have focused on biomarkers indicating underlying proteinopathy in cerebrospinal fluid and blood serum. However, due to the complexity and heterogeneity of neurodegenerative processes within the central nervous system and the large number of overlapping clinical diagnoses, identifying individual proteinopathies is relatively difficult and often not entirely accurate. For this reason, there is an urgent need to develop laboratory methods for identifying specific biomarkers, understand the molecular basis of neurodegenerative disorders and classify the quantifiable and readily available tools that can accelerate efforts to translate the knowledge into disease-modifying therapies that can improve and simplify the areas of differential diagnosis, as well as monitor the disease course with the aim of estimating the prognosis or evaluating the effects of treatment. The aim of this review is to summarize the current knowledge about clinically relevant biomarkers in different neurodegenerative diseases.

BACKGROUND: Thrombosis is linked to neutrophil release of neutrophil extracellular traps (NETs). NETs are proposed as a mechanism of resistance to thrombolysis. This study intends to analyze the composition of thrombi retrieved after mechanical thrombectomy, estimate the age and organization of thrombi, and evaluate associations with the use of thrombolysis, antiplatelets, and heparin. METHODS: This retrospective observational study involved 72 samples (44 from cerebral and 28 coronary arteries), which were stained with hematoxylin and eosin, anti-NE (neutrophil elastase) antibody, and anti-histone H2B (histone H2B) antibody, representing different components in NET formation, all detectable during the later stages of NETosis, for histochemical and digital quantification of NET content. The histological and morphological evaluations of the specimens were correlated, through univariate and mediation analyses, with clinical information and therapy administered before intervention. RESULTS: The results demonstrated that the composition of cerebral and coronary thrombi differs, and there were significantly more lytic cerebral thrombi than coronary thrombi (66% versus 14%; P =0.005). There was a considerably higher expression of NETs in the cerebral thrombi as testified by the higher expression of H2B ( P =0.031). Thrombolysis was remarkably associated with higher NE positivity (average marginal effect, 6.461 [95% CI, 0.7901–12.13]; P =0.02555), regardless of the origin of thrombi. There was no notable association between the administration of antiaggregant therapy/heparin and H2B/NE amount when adjusted for the thrombus location. Importantly, the age of the thrombus was the only independent predictor of NET content without any mediation of the thrombolytic treatment ( P =0.014). CONCLUSIONS: The age of the thrombus is the driving force for NET content, which correlates with impaired clinical outcomes. The therapy that is currently administered does not modify NET content. This study supports the need to investigate new pharmacological approaches added to thrombolysis to prevent NET formation or enhance their disruption, such as recombinant human DNase I (deoxyribonuclease I).

Neurodegenerative diseases are characterized by the deposition of specific protein aggregates, both intracellularly and/or extracellularly, depending on the type of disease. The extracellular occurrence of tridimensional structures formed by amyloidogenic proteins defines Alzheimer’s disease, in which plaques are composed of amyloid β-protein, while in prionoses, the same term “amyloid” refers to the amyloid prion protein. In this review, we focused on providing a detailed didactic description and differentiation of diffuse, neuritic, and burnt-out plaques found in Alzheimer’s disease and kuru-like, florid, multicentric, and neuritic plaques in human transmissible spongiform encephalopathies, followed by a systematic classification of the morphological similarities and differences between the extracellular amyloid deposits in these disorders. Both conditions are accompanied by the extracellular deposits that share certain signs, including neuritic degeneration, suggesting a particular role for amyloid protein toxicity.

Frontotemporal lobar degeneration with ubiquitin and TDP-43 positive neuronal inclusions represents a novel entity (FTLD-TDP) that may be associated with motor neuron disease (FTLD-MND); involvement of extrapyramidal and other systems has also been reported.

Despite an early understanding of amyotrophic lateral sclerosis (ALS) as a disease affecting the motor system, including motoneurons in the motor cortex, brainstem, and spinal cord, today, many cases involving dementia and behavioral disorders are reported. Therefore, we currently divide ALS not only based on genetic predisposition into the most common sporadic variant (90% of cases) and the familial variant (10%), but also based on cognitive and/or behavioral symptoms, with five specific subgroups of clinical manifestation—ALS with cognitive impairment, ALS with behavioral impairment, ALS with combined cognitive and behavioral impairment, the fully developed behavioral variant of frontotemporal dementia in combination with ALS, and comorbid ALS and Alzheimer’s disease (AD). Generally, these cases are referred to as amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD). Clinical behaviors and the presence of the same pathognomonic deposits suggest that FTLD and ALS could be a continuum of one entity. This review was designed primarily to compare neuropathological findings in different types of ALS relative to their characteristic locations as well as the immunoreactivity of the inclusions, and thus, foster a better understanding of the immunoreactivity, distribution, and morphology of the pathological deposits in relation to genetic mutations, which can be useful in specifying the final diagnosis.