Hyperphosphorylated Tau in Mesial Temporal Lobe Epilepsy: a Neuropathological and Cognitive Study.

Temporal lobe epilepsy (TLE) often courses with cognitive deficits, but its underlying neuronal basis remains unclear. Confluent data suggest that epilepsy share pathophysiological mechanisms with neurodegenerative diseases. However, as most studies analyze subjects 60 years old and older, it is challenging to rule out that neurodegenerative changes arise from age-related mechanisms rather than epilepsy in these individuals. To fill this gap, we conducted a neuropathological investigation of the hippocampal formation of 22 adults with mesial TLE and 20 age- and sex-matched controls (both younger than 60 years). Moreover, we interrogated the relationship between these neuropathological metrics and cognitive performance. Hippocampal formation extracted from patients with drug-resistant mesial TLE undergoing surgery and postmortem non-sclerotic hippocampal formation of clinically and neuropathologically controls underwent immunohistochemistry against amyloid ß (Aß), hyperphosphorylated tau (p-tau), and TAR DNA-binding protein-43 (TDP-43) proteins, followed by quantitative analysis. Patients underwent a comprehensive neuropsychological evaluation prior to surgery. TLE hippocampi showed a significantly higher burden of p-tau than controls, whereas Aß deposits and abnormal inclusions of TDP-43 were absent in both groups. Patients with hippocampal sclerosis (HS) type 2 had higher immunostaining for p-tau than patients with HS type 1. In addition, p-tau burden was associated with impairment in attention tasks and seizures frequency. In this series of adults younger than 60 years-old, the increase of p-tau burden associated with higher frequency of seizures and attention impairment suggests the involvement of tau pathology as a potential contributor to cognitive deficits in mesial TLE.

Metformin prevents p-tau and amyloid plaque deposition and memory impairment in diabetic mice.

Insulin deficiency or resistance can promote dementia and hallmarks of Alzheimer's disease (AD). The formation of neurofibrillary tangles of p-TAU protein, extracellular Aß plaques, and neuronal loss is related to the switching off insulin signaling in cognition brain areas. Metformin is a biguanide antihyperglycemic drug used worldwide for the treatment of type 2 diabetes. Some studies have demonstrated that metformin exerts neuroprotective, anti-inflammatory, anti-oxidant, and nootropic effects. This study aimed to evaluate metformin's effects on long-term memory and p-Tau and amyloid ß modulation, which are hallmarks of AD in diabetic mice. Swiss Webster mice were distributed in the following experimental groups: control; treated with streptozotocin (STZ) that is an agent toxic to the insulin-producing beta cells; STZ + metformin 200 mg/kg (M200). STZ mice showed significant augmentation of time spent to reach the target box in the Barnes maze, while M200 mice showed a significant time reduction. Moreover, the M200 group showed reduced GFAP immunoreactivity in hippocampal dentate gyrus and CA1 compared with the STZ group. STZ mice showed high p-Tau levels, reduced p-CREB, and accumulation of ß-amyloid (Aß) plaque in hippocampal areas and corpus callosum. In contrast, all these changes were reversed in the M200 group. Protein expressions of p-Tau, p-ERK, pGSK3, iNOS, nNOS, PARP, Cytochrome c, caspase 3, and GluN2A were increased in the parietal cortex of STZ mice and significantly counteracted in M200 mice. Moreover, M200 mice also showed significantly high levels of eNOS, AMPK, and p-AKT expression. In conclusion, metformin improved spatial memory in diabetic mice, which can be associated with reducing p-Tau and ß-amyloid (Aß) plaque load and inhibition of neuronal death.

Encefalopatía traumática crónica, definición, diagnóstico y prevención: revisión de la literatura / Chronic traumatic encephalopathy, definition, diagnosis and prevention: review of literature

La encefalopatía traumática crónica (ETC) es una enfermedad neurodegenerativa que se produce como consecuencia traumatismos cerebrales repetitivos; concusiones, que son un síndrome clínico que se caracteriza por una alteración de la función cerebral. Una concusión, bajo su estricta definición, no debiese causar cambios estructurales en el cerebro por lo que no sería visible a través de imágenes, sí existen cambios a nivel microscópicos, bioquímicos y biomecánicos. La mayoría de los pacientes tienen completa resolución de sus síntomas dentro de 10 días (90 por ciento), pero existe un pequeño porcentaje que persiste con estos, pudiendo presentarse como un síndrome postconcusional, síndrome de segundo impacto o una encefalopatía traumática crónica. La ETC se caracteriza por la acumulación de prot-tau hiperfosforilada en neuronas y astrocitos. Estas se van a presentar en forma de ovillos o hilos neurofibrilares. En etapas iniciales las encontraremos de forma focalizada en la corteza frontal y en las formas más severas su distribución será más generalizada, distribuyéndose en la mayoría de las regiones del cerebro. Su diagnóstico se realiza a través de histopatología, por lo que hasta el momento sólo se ha logrado post-mortem. Se está trabajando en nuevas tecnologías asociadas a biomarcadores y PET para lograr una diagnostico premortem. El mayor énfasis en el manejo de esta taupatía es la prevención y adecuado manejo de las concusiones.

Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease which is produced as a consequence of repeated brain trauma: concussions, which are a clinical syndrome characterized by an alteration in brain functions. A concussion, understrict definition, should not cause structural changes to the brain. Therefore, it would not be possible to see through images if there were changes at a microscopic, biochemical level. Most patients see their symptoms completely resolved within 10 days (90 percent), but there is a small percentage which persists, and these might cause a post-concussional syndrome, second impact syndrome of chronic traumatic encephalopathy. CTE is characterized by the accumulation of hyper-phosphorylated Tau protein in neurons and astrocytes. These appear in the form of neurofibrillary tangles. During the initial stages they are focalized in the frontal cortex and, in more severe cases, their distribution is more generalized, spreading through the majority of the regions in the brain. It is diagnosis is done through histopathology. Thus, it has only been possible to do post mortem. New technologies associated with bio-markers and PET are being worked on to achieve a pre-mortem diagnosis. The greatest emphasis in the handling of this tauopathy lies in the prevention and the adequate handling of concussions.