LATE: symptoms, causes and treatment of this dementia.

This new type of dementia has been confused for years with Alzheimer's disease.

If we talk about dementias, it is possible that a large number of names come to mind, but there is undoubtedly one name that stands out from all the others: Alzheimer's disease.

The deficits generated by this disease, highlighting the affectation it generates at the level of memory, and its typical evolution is something generally well documented and known not only by the scientific community but also by the general population.

However, Alzheimer's is not the only existing dementia, and we can also find some with similar symptoms and presentation styles. One of them, which in fact in the past was considered a subtype of Alzheimer's disease, has recently received the consideration of an independent clinical entity: we are talking about the TDO-43 limbic-predominant age-related encephalopathy or LATEwhich we are going to talk about in this article.

Age-related limbic-predominant TDP-43 encephalopathy (LATE): what is it?

The TDP-43 limbic-predominant age-related encephalopathy or LATE is a proteinopathy-type disease that generates a dementia highly similar to Alzheimer's disease, in which there are alterations in the brain and brain function.in which there are alterations in the TDP-43 protein. It is a disease that generates neurodegeneration, and is characterized by a progressive loss of cognitive abilities as brain cells degenerate and die.

Although this dementia has only recently been identified, it is estimated that between 20 and 50% of people over 80 years of age may in fact suffer from it. It is more common in women, although it should also be noted that life expectancy over the age of 80 is much lower in men. It has often been confused with Alzheimer's disease, although early research identified it as a subtype of Alzheimer's disease. However, it is a different condition.

LATE dementia dementia is especially known to cause severe hippocampal involvement.Although the first manifestations usually affect the limbic pathways. The resulting dementia is characterized by amnestic involvement, and gradually, as the disease progresses, other areas of the brain and other cognitive functions are affected.

The progression of this dementia is much slower than in other neurodegenerative pathologies, but it can be associated with others and in this case worsens the picture.but it can be associated with others and in this case worsens the picture.

Progression in 3 phases

Although more research is needed, studies conducted so far seem to indicate the existence of three major stages through which the disease evolves and generates more and more affectation. In fact, there are several proposed classifications, but in general, the following consensus classification is usually taken as a reference.

Phase 1: Tonsillar involvement

Contrary to what happens in other dementias, one of the first areas affected by dementia caused by LATE is the amygdala, being initially an involvement that occurs specifically in this brain region. This involvement can generate alterations at the mood level.and, according to studies, there is a tendency to agitation and even aggressiveness in patients at this stage.

Stage 2: Hippocampal involvement

In a second phase the hippocampus begins to be affected by the encephalopathy. In this phase memory is more compromised, and although it is not usually the first area affected, it is the most recognized alteration.

There is gliosis and neuronal lossIn addition, it is possible that sclerosis may appear comorbidly at the hippocampal level and there may even be asymmetry between both hemispheres. Astrocytosis and involvement of the entorhinal cortex with hypertrophied microglia may also be seen. In addition, the dentate gyrus, occipitotemporal gyrus, insula and inferior olive also degenerate at this stage.

Stage 3: Involvement of the medial frontal gyrus.

In this third stage, behavioral and behavioral disturbances are manifested, also causing severe impairment of activities of daily living that may even be more severe than in other dementias. In addition to this region the frontal and temporal regions are also affectedThe frontal and temporal regions are also affected, which leads to the appearance of symptoms similar to those of advanced Alzheimer's disease. Subcortical degeneration is also common, especially in the basal ganglia.

Causes

The causes of LATE, as with most other dementias, are not fully known and understood. However, it has been observed as an aspect linked to its appearance is the presence in different points of the brain of accumulations of TDP-43 protein.

This protein is part of our body and is of great help when it comes to the genes linked to the development and functioning of the brain are expressed correctly, but nevertheless However, when unfolded and in excess, this protein may be neurotoxic and generate neurodegeneration and the decrease of different cognitive abilities (including memory).

This factor also appears in other pathologies, but it is a quite relevant differential factor with respect to Alzheimer's disease. Furthermore, in age-related limbic-predominant TDP-43 encephalopathy, there are no visible alterations of the TAU protein, something that abounds in Alzheimer's disease in the form of the generation of neurofibrillary tangles that hinder synaptic transmission.

Another risk factor, as its full name indicates, is age.This problem has been observed in people whose age ranged between seventy and eighty years of age, and its probability of occurrence increases as the years go by. Several genetic analyses have also been carried out and the presence of mutations in genes such as GRN, APOE, and TMEM106B also appear to be risk factors.

Alzheimer's disease and LATE: two easily confused diagnoses

At the level of symptomatology, dementia caused by the encephalopathy known as LATE is apparently very similar to Alzheimer's diseaseFor this reason, it has not been identified as an entity distinct from Alzheimer's disease until now. In fact, the discovery of this pathology suggests that many of the cases diagnosed with Alzheimer's actually suffered from this recently discovered problem.

One of the main differences can be found at the neurobiological level, as mentioned in the previous section: while in Alzheimer's disease there are accumulations of TAU protein in LATE there are no major alterations in this protein, while there are in the TDP-43 protein (something that is not common in Alzheimer's disease).

Likewise, although both pathologies affect brain regions such as the amygdala, the hippocampus and the middle frontal gyrus, the order of presentation is different: in LATE the onset of degeneration is seen at the amygdala level, while in Alzheimer's it is the temporal lobe and the hippocampus that begin to degenerate.

But although they are different entities, it is also true that TDP-43 encephalopathy may appear in association with other disorders, including Alzheimer's disease (also amyotrophic lateral sclerosis and frontal dementias). In this sense, although the neurodegeneration caused by LATE is much more gradual than in Alzheimer's disease when it occurs alone. is much more gradual than in Alzheimer's disease when it occurs alone, the process of neurodegeneration is much faster than in either condition alone.When both pathologies appear together, the neurodegeneration process is much faster than in either of the two conditions separately.

In search of a treatment

There is currently no well-established treatment for this dementia, but the fact that it works differently from Alzheimer's disease may explain why many of the pharmacological treatments for what were thought to be cases of this disease are unsuccessful.

Mechanisms and techniques to combat this disease should be explored.The main focus is likely to be on combating the excessive accumulation of TDP-43 protein. Likewise, once the existence of symptomatological differences with Alzheimer's disease has been analyzed to a greater extent, more specific training and cognitive stimulation programs could be developed, although on the other hand, the programs already developed are not specifically focused on Alzheimer's disease but on the fight against the symptoms it generates, which in this sense are largely shared.

Bibliographical references

• Nelson, P.T., Dickson, D.W., Trojanowski, J.Q., Jack, C.R., Boyle, P.A., Arfanakis, K., Rademakers, R., Alafuzoff, I., Attems, J., Brayne, C., Coyle-Gilchrist, I.T.S., Chui, H.C., Fardo, D.W., Flanagan, M.E., Halliday, G., Hokkanen, S.R.K., Hunter, S., Jicha, G.A., Katsumata, Y., Kawas, C.H., Keene, C.D., Kovacs, G.G., Kukull, W.A., Levey, A.I., Makkinejad, N., Montine, T.J., Murayama, S., Murray, M.E., Nag, S., Rissman, R.A., Seeley, W.W., Sperling, R.A., White III, C.L., Yu, L. & Schneider, J.A. (2019). Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain, awz99.