VALIDACIÓN POR EXPERTOS

This section explains the development stages of NDDs, and the symptoms that appear at each stage. We also discuss how we can detect neurological diseases from the pre-clinical stage to their last stage. The development cycle of neurodegenerative diseases is divided into three main stages:

1. Retrogenesis;

3. Gait Abnormality;

Retrogenesis: The starting point of NDDs is a malfunctioning of the cholinergic system of the basal fore brain, which further extends to the Entorhinal Cortex and the Hippocampus that are responsible for the short and the long term memory [2]. These changes in the brain usually start 10-20 years in advance and the first visible sign of NDDs is forgetfulness or some problems in short term memory, e.g., forgetting the place for eye-glasses, everyday objects, misplacing the keys, etc. Symptoms may include enhanced memory loss, attention loss, difficulties in recognizing the family members, needing help in getting dressed and also gait problems.

The disease with its progression starts affecting the cerebral cortex resulting in the form of further decrease in cognitive power. This stage is linked with the clinical diagnosis of NDDs in patients which include confusing among familiar places, losing decision power, mis- placing valuable things, mood and personality changes, childish actions in office, increased anxiety, loss of spontaneity and sense of initiatives [2, 44].

Further atrophy in the affected area of the cerebral cortex results in the form of serious problems with language, sensory neurons and reasoning. Patients show serious attitude towards wandering and agitation. Symptoms may include enhanced memory loss, attention loss, difficulties in recognizing family members, needing help in getting dressed and also gait problems.

Figure 2-1: Manifestation of pathology and its progression in AD

Figure 2-1, shows the process of retrogenesis where the darker areas depict the affected parts of the brain. Similarly, this process of retrogenesis has been elaborated in Table 2-1, which shows the process of normal human brain development compared to the deterioration of brain cells due to neurodegenerative diseases. Here, the upward arrow indicates the development process and the downward arrow shows the destruction of brain parts.

Table 2-1: Brain Development vs. Brain Deterioration

Human Development Stages Vs. Alzheimer’s Stages

Developmental Stages Acquired Abilities Alzheimer’s Stages Lost Abilities

Adolescence-to-

Puberty

Work nicely without help

Develop working skills

Manage routine works accurately

Preclinical-to-

Early Stage

Work with less confidence

Losing focus on skills

Minor mistakes in work

Mid Childhood –to- adolescence

Get good memory

Try to learn complex tasks

Managing with clothing and food

Good understanding

Early Stage-to-

Mild Stage

Forgetting little things

Cannot handle complex tasks

Difficulty in managing food and getting dressed

Early Childhood-to-

Mid Childhood

Walk steadily

Try to do small tasks

Manage to put on cloths

Taking shower on their own

Mild Stage-to-

Moderate Stage

Disturbance in walking

Cannot perform small tasks

Cannot take shower on their own Infancy-to- Early Childhood Holding up head Trying to sit Smile Shaky walk Try to speak Moderate Stage-to- Severe Stage Speaking problems Cannot walk Loss of memory

Cannot hold-up their head

Cognitive Impairment: There is a very close relationship between neuro-degeneration and toxic proteins. This stage is accompanied with the accumulation of pathological

neurofibrillary plaques and tangles in the entorhinal cortex (EC), hippocampus, caudate, substantia nigra parts of the brain. These proteins play a pathogenic role in the progression of NDDs which results in the form of neurons degeneration and memory impairments. The Entorhinal Cortex (EC) is that part of the brain which gets affected due to Alzheimer’s. Neuroscientists have reported that in order to keep memory alive the communication between the Entorhinal Cortex (EC) and the Hippocampus is very essential and any hurdle between these two regions breaks the circuit and leads towards memory disturbance and memory loss. It is concluded that EC is the main hub which is more vulnerable to NDDs and these diseases propagate with the network of neurons [3].

Our research work shows that accumulation of these pathological proteins is another factor, which could help with the early prediction of Alzheimer’s and other neurodegenerative diseases.

Gait Abnormality: Predicting a disturbance in gait activity indicates a disturbance in cognitive functions. Scherdera et al [45] have proposed a term “Last-in-First-out” which refers to the phenomenon that the neural circuits that mature late in the developmental life cycle are more vulnerable to neuro-degeneration and this concept helps in early prediction of any kind of dementia (Neurodegenerative diseases). Zhu et al [46] stated that a healthy gait pattern requires input not only from the neurological system associated with motor and sensory neurons but also from cortical processes such as judgment, planning and a spatial awareness. Higher level gait disturbances are under consideration these days, which are closely related to disturbances in cortico-cortical and cortico-subcortical connections, e.g., the frontal connection with parietal lobes and frontal lobes with basal ganglia, respectively [4]. Disturbances in cognitive function have a direct link with higher level gait disturbances and it is one of the main symptoms of brain disease. Figure 2-2 elaborates the relationship between neurological diseases and their effects on body movements.

Figure 2-2: Relationship between cerebral pathology and gait disorder [47]